AJP - Endo Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 293: E75-E82, 2007. First published March 13, 2007; doi:10.1152/ajpendo.00689.2006
0193-1849/07 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/E75    most recent
00689.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by De Blasio, M. J.
Right arrow Articles by Owens, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Blasio, M. J.
Right arrow Articles by Owens, J. A.

Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring

M. J. De Blasio,1 M. Dodic,2 A. J. Jefferies,2 K. M. Moritz,2 E. M. Wintour,2 and J. A. Owens1

1Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide; and 2Department of Physiology, Monash University, Clayton, Victoria, Australia

Submitted 18 December 2006 ; accepted in final form 5 March 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
An adverse intrauterine environment increases the risk of developing various adult-onset diseases, whose nature varies with the timing of exposure. Maternal undernutrition in humans can increase adiposity, and the risk of coronary heart disease and impaired glucose tolerance in adult life, which may be partly mediated by maternal or fetal endocrine stress responses. In sheep, dexamethasone in early pregnancy impairs cardiovascular function, but not glucose homeostasis in adult female offspring. However, male offspring are often more susceptible to early life "programming". Pregnant sheep were infused intravenously with saline (0.19 ml/h), dexamethasone (0.48 mg/h), or cortisol (5 mg/h), for 2 days from 26 to 28 days of gestation. In male offspring, size at birth and postnatal growth were measured, and glucose tolerance [intravenous glucose tolerance test (IVGTT)], insulin secretion, and insulin sensitivity of glucose, {alpha}-amino nitrogen, and free fatty acid metabolism were assessed at 4 yr of age. We show that cortisol, but not dexamethasone, treatment of mothers causes fasting hyperglycemia in adult male offspring. Maternal cortisol induced a second-phase hyperinsulinemia during IVGTT, whereas maternal dexamethasone induced a first-phase hyperinsulinemia. Dexamethasone improved glucose tolerance, while cortisol had no impact, and neither affected insulin sensitivity. This suggests that maternal glucocorticoid exposure in early pregnancy alters glucose homeostasis and induces hyperinsulinemia in adult male offspring, but in a glucocorticoid-specific manner. These consequences of glucocorticoid exposure in early pregnancy may lead to pancreatic exhaustion and diabetes longer term and are consistent with stress during early pregnancy contributing to such outcomes in humans.

glucose tolerance; disposition index

THE INTRAUTERINE ENVIRONMENT is a major determinant of fetal growth and of risk of metabolic disease in the adult human (29, 56). This link suggests that adverse perturbations of the fetal environment, such as limited oxygen and nutrient supply, restrict growth and induce long-term alterations in the structure and function of key tissues involved in homeostasis, leading to adult onset diseases (5, 6). The developmental timing of exposure to such challenges in utero also appears to influence the nature of the subsequent impairment to health (52, 54, 55).

The offspring of women exposed to famine at any stage during pregnancy develop hyperinsulinemia and impaired glucose tolerance, although this is most marked in those exposed late in gestation once in their fifties (14, 50, 52–55). Exposure in early pregnancy to the Dutch Winter Hunger Famine was additionally characterized by obesity, an atherogenic profile, and increased incidence of coronary heart disease in adult offspring (14, 50, 52–55, 68). Maternal undernutrition in early pregnancy remains a common challenge due to morning sickness or hyperemesis gravidarum and may similarly impact on the fetus. It has been proposed that endocrine responses of mothers and their offspring exposed to nutritional restriction may partly mediate the programming of later dysfunction (54). Women who experience hyperemesis gravidarum (severe morning sickness resulting in continual vomiting and hence undernutrition) exhibit increased circulating cortisol compared with nonhyperemesis women or nonpregnant women (34, 67). Such increases in circulating cortisol (1, 3, 39) may increase the exposure of the fetus to glucocorticoids. This may also occur when exogenous steroids are administered to the mother for conditions such as asthma and congenital adrenal hyperplasia (12, 37, 43), in association with reduced placental concentrations of 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD-2) (57). The developing fetal tissues are usually protected from high levels of maternal glucocorticoids by the actions of 11beta-HSD-2 in the placenta or the fetal tissues themselves (7, 21, 57), which converts most (but not all) cortisol into an inactive form. Undernutrition in the rat and sheep at least downregulates placental 11beta-HSD-2, however (9, 38, 42, 70), which, if it occurs in women, may further increase fetal exposure to maternal glucocorticoids. The aim of this study was to mimic a short-term stressful experience, such as morning sickness or a period of short-term undernutrition occurring during early gestation, by briefly exposing the mother to exogenous glucocorticoids at that stage and determining the outcomes for glucose homeostasis and insulin action in offspring. Certainly, maternal dexamethasone exposure in late gestation produces fasting hyperglycemia and/or glucose intolerance and an increased glucose-stimulated insulin secretion in adult offspring in the rat and sheep (20, 44, 46). In the rat, administration throughout pregnancy with carbenoxolone (an inhibitor of 11beta-HSD) allows an increase in the passage of the natural glucocorticoid cortisol, reduces birth weight, and also impairs glucose tolerance in adult offspring (40, 41). But whether maternal exposure to glucocorticoids in early gestation at different developmental stages in the fetus induces similar outcomes is largely unknown. Maternal dexamethasone induces the former, in part by increased hepatic levels of gluconeogenic enzymes, such as the rate-limiting enzyme phosphoenolpyruvate carboxykinase (PEPCK) (20, 46).

An additional aim was to assess to what extent any outcomes result directly from fetal exposure to glucocorticoids that cross the placenta or are indirect consequences of maternal and placental glucocorticoid exposure (28, 44). The effects of the synthetic glucocorticoid dexamethasone (which can cross the placental barrier to the fetal tissues without inactivation and acts on the glucocorticoid but not the mineralocorticoid receptor) and the natural glucocorticoid cortisol (which is partly inactivated by the placental barrier and acts on both receptors in fetal tissues) were, therefore, compared. Differential effects of maternal exposure to dexamethasone and cortisol have been demonstrated in sheep, where exposure to dexamethasone, but not cortisol or saline, in early pregnancy (27–29 days of gestation) increased responsiveness of central nervous system angiotensinergic mechanisms in response to angiotensin II and decreased heart rate and cardiac output (19). We, therefore, propose that maternal dexamethasone exposure will alter glucose homeostasis and insulin action and related parameters to a greater extent than cortisol in offspring.

There is also evidence from a range of species and experimental prenatal challenges to suggest that males are more sensitive to early life programming of insulin action than are females (23, 36). Males appear more susceptible to perinatal programming of metabolic and cardiovascular homeostasis than females in humans and in experimental models of fetal growth restriction (23, 64). At 20 yr of age following intrauterine growth restriction in humans, insulin sensitivity was reduced in men but not women who were light or short at birth (23). Early life influences also accounted for a greater proportion of variance in metabolic syndrome score at 50 yr of age in men than women, and birth weight and catch-up growth in childhood were related to metabolic score and to fasting insulin, respectively, in men, but not women, at 50 yr of age, suggesting that males are more susceptible to early life influences (51). We have previously shown that female offspring of pregnant ewes exposed to dexamethasone treatment in early pregnancy (27–29 days of gestation) also had increased insulin sensitivity of lipolysis, but unaltered glucose homeostasis or insulin action at 5 yr of age (25). We propose that, in contrast, maternal exposure to dexamethasone in early pregnancy will affect glucose control and insulin action in male offspring.

We, therefore, assessed insulin and glucose homeostasis in adult male offspring following short-term maternal exposure to dexamethasone, cortisol, or vehicle in early pregnancy from 26 to 28 days of gestation (~0.2 gestation). This is equivalent to ~50 days of gestation in the human and corresponds to the end of the human embryonic period. We hypothesized that maternal exposure to dexamethasone in early pregnancy would reduce size at birth; program fasting hyperglycemia, hyperinsulinemia, and hypoaminoacidemia, the latter partly due to increased gluconeogenesis; and impair glucose tolerance in male offspring compared with exposure to saline. We further hypothesized that maternal dexamethasone exposure in early pregnancy would impair insulin secretion in response to glucose and insulin sensitivity of glucose metabolism, but enhance that of lipolysis in male offspring. We further hypothesized that maternal cortisol exposure would have similar consequences, but of a lesser magnitude compared with dexamethasone for glucose homeostasis, insulin action, and related parameters in male offspring.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All experiments were approved by the Animal Ethics Committee of Monash University before commencement of experimental protocols.

Pregnant ewes were treated with dexamethasone (Decadron; Merck, Sharp and Dohme) (0.48 mg/h), cortisol (5 mg/h), or saline (0.19 ml/h), given as an intravenous infusion for 48 h from 26 to 28 days of gestation. Ewes were allowed to lamb naturally. Adult male singleton offspring were castrated and tail docked at 2 mo of age and had carotid artery loops constructed under general anesthesia at ~1 yr of age (18). Male offspring were housed in metabolic crates and provided 0.8-kg lucerne chaff per day and water ad libitum, but were fasted overnight before the hyperinsulinemic euglycemic clamp (HEC) (4.08 ± 0.89 yr of age) and intravenous glucose tolerance tests (IVGTTs) (4.26 ± 0.89 yr of age).

Growth measures. Size at birth in terms of weight, crown-rump length, abdominal circumference, and placental weight was measured. Weight was measured in adult male offspring the day before the HEC.

HEC and insulin sensitivity of glucose metabolism. At 4.08 ± 0.89 yr of age, a HEC was performed. Sheep were weighed and then fasted overnight and allowed water ad libitum throughout. Arterial blood was sampled (2 ml) at –10, –5, and 0 min; human insulin (Actrapid, Novo Nordisk) was then continuously infused intravenously (4 mU·kg–1·min–1); and blood was sampled (0.2 ml) every 5 min for 120 min. Blood glucose at each time point was measured using a HemoCue glucometer (HemoCue). At 15 min after the start of the insulin infusion, glucose (25%) was infused intravenously, initially at 2 mg·kg–1·min–1. The glucose infusion rate (GIR) was then adjusted each 5 min after the measurement of blood glucose, to maintain euglycemia at the fasting blood glucose concentration, using a modification of a previously published algorithm (15, 25). The mean coefficient of variation (CV) in blood glucose during the second hour of the clamp was 10.1%. Plasma insulin was measured before the start of HEC (–10, –5, 0 min) and during the second hour of the HEC (60, 75, 90, 105, 120 min), to determine the fasting plasma insulin concentration and the plateau plasma insulin concentration achieved, respectively. The insulin sensitivity of whole body glucose metabolism was determined as the mean GIR from 60 to 120 min during the HEC, divided by the mean plasma insulin concentration in the second hour of infusion measured every 15 min. The mean CV for GIR from 60 to 120 min in each lamb during the HEC was 38.2%.

Insulin sensitivity of circulating amino acids. Plasma {alpha}-amino nitrogen concentration was measured before and during the second hour of the HEC (–10, –5, 0, 60, 75, 90, 105, 120 min) by colorimetric assay (22). The insulin sensitivity of circulating amino acids was calculated as the percentage change from fasting plasma {alpha}-amino nitrogen concentrations to those during the second hour of the HEC, corrected for the plateau plasma insulin concentration.

Insulin sensitivity of circulating free fatty acids. Plasma free fatty acid (FFA) concentration was measured before and during the second hour of the HEC (–10, –5, 0, 60, 75, 90, 105, 120 min) by enzymatic analysis. The insulin sensitivity of circulating plasma FFA was calculated as the percentage change from fasting FFA concentrations to those during the second hour of the HEC, corrected for the plateau plasma insulin concentration.

Insulin clearance and posthepatic insulin secretory rate. Insulin clearance was calculated as the rate of insulin infusion during the HEC divided by the plateau plasma insulin concentration achieved in the second hour of the clamp. Posthepatic insulin secretory rate in the basal state was calculated as the fasting plasma insulin concentration before the IVGTT multiplied by the insulin clearance rate.

Disposition index. The disposition index is a measure of insulin action, reflecting both insulin abundance and sensitivity, and was calculated for glucose, amino acid, and FFA metabolism as the posthepatic insulin delivery rate in the fasting state multiplied by the insulin sensitivity of glucose, amino acids, or FFA metabolism (24, 49).

Insulin secretion in response to IVGTT. At 4.26 ± 0.89 yr of age, an IVGTT was performed. Sheep were fasted overnight before the experiment, but were allowed water ad libitum. Arterial blood samples (5 ml) were taken at –5, –3, 0, 2, 5, 10, 15, 20, 25, 30, 40, 60, 70, 80, 90, 100, 120, 140, 160, 180, and 210 min. At 0 min, 0.25 g glucose/kg live weight was rapidly infused intravenously over 30 s. Blood glucose concentration at each time was measured using a HemoCue glucometer. The remaining blood was centrifuged, and plasma was collected for measurement of plasma glucose and insulin concentrations. Fasting plasma glucose and insulin concentrations are the mean of the concentrations of the first three time points before glucose administration. Insulin secretion during the IVGTT was calculated as the area under the insulin concentration curve vs. time. Areas under the glucose and insulin curves, with the mean of the fasting concentrations as the baseline, were calculated using the Sigma Scan Pro v4 image analysis software package (Jandel Scientific Software).

Analysis of plasma metabolites and hormones. Plasma glucose, triglycerides, and cholesterol concentrations were measured by enzymatic analysis with a COBAS MIRA automated sample system, using the Glucose HK assay kit, Triglyceride kit, and Cholesterol kit, with the calibrator for automated systems, and quality controls: Precinorm U and Precipath U (Roche Diagnostics, Peakhurst, NSW, Australia). The mean CV for each individual assay was <3.3%. The quantitative determination of plasma FFAs was performed with a COBAS MIRA automated sample system using the NEFA-C FFA assay kit (Wako Pure Chemical Industries, Japan, intra-assay CV, 4%) and quality controls: QCS 1 and 2 (Bio-Rad, Australia). The mean CV for the assay of plasma FFAs was <4.6%. Plasma {alpha}-amino nitrogen concentrations were measured by deproteinizing 100 µl of plasma with 800 µl of 0.04 M H2SO4 and 100 µl of 0.3 M sodium tungstate. These were centrifuged for 15 min at 3,000 g, and 100 µl of supernatant were placed into a 96-well plate. To this, 24 µl sodium tetraborate (saturated, pH 9.6 with 5 M NaOH) and 20 µl 0.02 M beta-naphthoquinone sulfonate were added and incubated for 20 min at 80°C, then cooled in ice water for 5 min. Water (120 µl), 36 µl of acid formaldehyde (0.6 M HCl, 0.045 M HCHO), and 20 µl of 0.05 M sodium thiosulphate were added and incubated at room temperature for 30 min. The absorbance was read at 490 and 690 nm on an ELISA plate reader. Plasma insulin was measured using a commercially available radioimmunoassay kit (Linco, Australian Laboratory Services).

Statistical analysis. Data are expressed as means ± SE. Pearson correlation analysis, multiple linear regression analysis, and between-factor ANOVA (3 levels) with Tukey's post hoc test (SPSS 13.0 software package for Windows; SPSS, Chicago, IL) were used to test the overall effects of maternal exposure to glucocorticoids and specific a priori hypotheses that effects of cortisol would be of less magnitude than those of dexamethasone, as stated in the Introduction. The %CV was calculated as the standard deviation divided by the mean multiplied by 100. Statistical significance was assumed at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Size at birth and postnatal growth rate. Prenatal treatment of glucocorticoids did not alter birth weight or placental weight in either group (Table 1). Prenatal treatment with dexamethasone reduced abdominal circumference at birth (dexamethasone: 35.9 ± 0.7 cm, saline: 39.8 ± 1.2 cm, P = 0.02) compared with saline (Table 1). Prenatal treatment of glucocorticoids also did not alter live weight at 4.5 yr of age (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1. Effect of maternal dexamethasone and cortisol on size at birth and growth of male adult offspring

 
Birth weight and plasma glucose and insulin. Plasma glucose [saline: nonsignificant (NS); dexamethasone: NS; cortisol: r = 0.67, P < 0.05] and insulin (saline: NS; dexamethasone: NS; cortisol: r = 0.65, P < 0.05) correlated negatively with birth weight in cortisol-treated offspring only (Fig. 1).


Figure 1
View larger version (13K):
[in this window]
[in a new window]

  		Fig. 1. Effect of maternal glucocorticoid exposure in early pregnancy on the association of fasting plasma glucose (top) and insulin (bottom) with birth weight in offspring. Fasting plasma glucose [saline: nonsignificant (NS); dexamethasone: NS; cortisol: r = 0.67, P < 0.05] and insulin (saline: NS; dexamethasone: NS; cortisol: r = 0.65, P < 0.05) correlated negatively with birth weight in offspring exposed to cortisol only. Saline (bullet, solid line), dexamethasone ({square}, long dashed line), and cortisol ({triangleup}, short dashed line) infused ewes are shown.

 
Glycemia and insulin action on glucose metabolism. Maternal treatment with cortisol, but not dexamethasone, increased fasting plasma glucose concentration compared with saline (P < 0.05) (Fig. 2). Maternal dexamethasone reduced the area under the plasma glucose concentration curve during the IVGTT (P = 0.03) and reduced plasma glucose concentrations early (45–80 min) and late (120–140 min) during the IVGTT compared with saline (P < 0.05) (Fig. 3).


Figure 2
View larger version (19K):
[in this window]
[in a new window]

  		Fig. 2. Maternal glucocorticoid exposure in early pregnancy and the fasting plasma glucose, insulin, and plasma insulin-to-glucose ratio in adult male offspring. Saline is represented by solid bars, dexamethasone is represented by light gray bars, and cortisol is represented by dark gray bars. Data are presented as means ± SE. *P < 0.05.

 

Figure 3
View larger version (20K):
[in this window]
[in a new window]

  		Fig. 3. Maternal glucocorticoid exposure in early pregnancy and plasma glucose (top) and insulin (bottom) secretion in response to an intravenous glucose tolerance test in adult male offspring. Mean plasma glucose and insulin concentration curves from intravenous glucose tolerance tests (0.25 g/kg glucose bolus) are shown for offspring of saline (bullet), dexamethasone ({square}), and cortisol ({triangleup}) treated mothers from baseline (–10, –5, 0 min) to 210 min. The glucose bolus is administered at 0 min. The first- (0–30 min) and second-phase (30–210 min) insulin secretion are displayed. Data are presented as means ± SE, determined by addition of time as a repeated-measures factor (22 levels) by ANOVA. Individual contrasts are shown: *P < 0.05 for saline compared with dexamethasone, #P < 0.05 for saline compared with cortisol.

 
Maternal treatment with cortisol, but not dexamethasone, increased fasting plasma insulin concentrations, the fasting plasma insulin-to-glucose ratio (P < 0.05) (Fig. 1), and the basal posthepatic insulin delivery rate (P = 0.02) compared with saline (Table 2). Maternal dexamethasone increased plasma insulin concentrations from baseline until 30 min after glucose load, compared with saline (P < 0.05), indicative of a pronounced first-phase hyperinsulinemia (Fig. 3). Maternal treatment with cortisol did not alter plasma insulin concentrations during first-phase insulin secretion (from 2 to 30 min), but increased that from 40 to 140 min, compared with saline (P < 0.05), indicating a pronounced second-phase hyperinsulinemia (Fig. 3). Maternal dexamethasone also increased the insulin-stimulated glucose disposition index compared with saline (P = 0.04) (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2. Effect of maternal dexamethasone and cortisol on insulin sensitivity and secretion in male adult offspring

 
Other metabolites and insulin action. Maternal glucocorticoid treatment in early pregnancy did not alter fasting plasma FFAs, triglycerides, or cholesterol in adult male offspring (Table 3). Overall, fasting plasma triglycerides correlated positively with plasma insulin (r = 0.41, n = 21, P = 0.033), the basal insulin-to-glucose ratio (r = 0.38, n = 21, P = 0.045), the fasting posthepatic insulin delivery rate (r = 0.44, n = 21, P = 0.023), and the fasting glucose disposition index (r = 0.36, n = 21, P = 0.050). When treatment groups were analyzed separately, these correlations were present only in the offspring of saline-treated mothers (data not shown).


View this table:
[in this window]
[in a new window]

  		Table 3. Effect of maternal dexamethasone and cortisol on fasting plasma metabolites in male adult offspring

 
Glucocorticoids did not alter insulin sensitivity of glucose, FFA, or amino acid metabolism of adult male offspring (Table 2). Maternal glucocorticoid treatment reduced fasting plasma {alpha}-amino nitrogen concentrations compared with saline (P < 0.05) (Table 3), while the fasting and stimulated {alpha}-amino nitrogen disposition indexes were unaltered (data not shown).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study has demonstrated that maternal exposure to glucocorticoids for a short period in early pregnancy alters metabolic homeostasis and insulin action in male adult sheep offspring. Specifically, the short 2-day infusion of cortisol into the pregnant sheep caused fasting hyperglycemia and hyperinsulinemia, while the infusion of dexamethasone caused a hyperinsulinemic response to glucose in adult male offspring. Maternal treatment with dexamethasone induced a marked first-phase hyperinsulinemia and improved glucose tolerance. In contrast, maternal cortisol treatment induced a second-phase hyperinsulinemia with no impact on glucose tolerance, while neither glucocorticoid affected insulin sensitivity. These outcomes are similar to those of offspring of mothers exposed to the Dutch Famine in early gestation, who did not develop impaired glucose tolerance as adults, but were hyperinsulinemic compared with unexposed people (14, 52). Therefore, glucocorticoid exposure in early pregnancy in the sheep is able to alter insulin abundance and secretion in adult male offspring, and in a manner that suggests it could lead to diabetes and other related disorders later on. Altered glucose homeostasis and insulin secretion in offspring following maternal glucocorticoid exposure in late gestation has been shown in several species such as the rat and also sheep (33, 44, 46), and here we have shown that similar consequences arise in adult male sheep from maternal glucocorticoid exposure in early gestation.

The hyperinsulinemia induced in adult male offspring by maternal glucocorticoid exposure in early gestation reflects altered insulin secretion, independent of insulin sensitivity, as the latter was unchanged and insulin action on glucose metabolism was increased, following dexamethasone at least. This suggests persistent effects on insulin secretion and the developing pancreas of glucocorticoids administered to the pregnant sheep from 26–28 days of gestation (~0.2 gestation). Little is known of ovine pancreatic development at this time, however, and whether direct effects of glucocorticoids on the endocrine pancreas or indirect consequences of maternal exposure are involved requires further investigation.

The differential effects of early gestation exposure of the mother to cortisol or dexamethasone on insulin secretion in offspring in adult life may arise from targeting of determinants of different phases of insulin secretion. Here we have shown that maternal dexamethasone treatment in early gestation increases the first-phase insulin secretion in response to a glucose load for a given insulin sensitivity in offspring, suggesting there is clear over-secretion of insulin, whereas cortisol induces similar changes in second-phase insulin secretion. The release of insulin from the pancreas is biphasic in nature, such that the first-phase insulin release in response to glucose is the result of the exocytosis of a small pool of granules from the beta-cell within the pancreas (2, 13, 32, 71). This initial spike of insulin release is triggered by the glucose-induced closure of ATP-sensitive potassium channels and activation of their signaling pathway, which depolarizes the beta-cell to cause entry of calcium via voltage-dependent calcium channels (2, 13, 32, 71). Whether glucocorticoid exposure can affect any of these processes directly in the adult or earlier during development is unknown. The second-phase insulin secretion is incompletely understood, but requires a continuously elevated calcium and amplification of calcium action on exocytosis by ATP-sensitive potassium channel-independent mechanisms, as does the first phase to recruit vesicles from the reserve pool (47). The mechanism responsible for this is still unknown, but hypotheses include time-dependent changes in the concentration of signaling molecules (45), the time taken for the physical recruitment of vesicles to a ready reserve pool (48), or the recruitment of vesicles by other mechanisms (4). Recently, it has been suggested that alterations in either first- or second-phase insulin secretion may arise from changes in the size of the insulin-containing vesicle reserve pool in beta-cells (30); however, the differential effects of each glucocorticoid suggest other processes are targeted. There is little information as to glucocorticoid effects on these various determinants of the dynamics of insulin secretion in any species to date, however. Glucocorticoid exposure of pregnant rats in late gestation also produces hyperglycemia and hyperinsulinemia in offspring, and the former appears due to alterations in hepatic glucose production by the liver via increased PEPCK (a key enzyme in gluconeogenesis) gene expression (46). Notably, we have also shown that exposure to maternal cortisol in early pregnancy induced hyperglycemia in adult male offspring, which may act via a similar pathway. Here, maternal exposure in early pregnancy to either glucocorticoid consistently decreased plasma {alpha}-amino nitrogen concentrations in adult male offspring compared with saline. This may be related to the fasting hyperglycemia observed in offspring of the cortisol-treated ewes, through increased utilization of gluconeogenic amino acids for increased glucose production. Previous studies have shown that treating pregnant rats in late gestation with dexamethasone results in offspring with reduced birth weight and hyperinsulinemia and hyperglycemia, due to elevated levels of gluconeogenic enzymes, such as the rate-limiting enzyme PEPCK (20, 46). De novo synthesis of glucose utilizes amino acids (all amino acids are available except leucine) as major substrates, and inhibition of PEPCK and gluconeogenesis in the rat results in hypoglycemia and increased plasma amino acid concentration (69).

The origins of glucocorticoid-specific differences in these outcomes of maternal exposure in early pregnancy are unclear. Both dexamethasone and cortisol are able to cross the placenta in rats (8, 40, 46, 58) and sheep (16, 17, 35) and lead to adverse outcomes for adult offspring, but the extent to which each glucocorticoid actually crosses the placenta into the fetal circulation and accesses fetal tissues in early gestation is unknown. Dexamethasone is poorly metabolized by 11beta-HSD-2 and, therefore, most readily crosses the placenta (11, 59). Therefore, it seemed likely that the placenta and fetal tissues would have a greater glucocorticoid exposure following dexamethasone compared with cortisol in the present study. We found instead that maternal cortisol exposure increased fasting plasma glucose and insulin concentrations in adult male offspring to a greater extent than did dexamethasone, suggesting that these barriers were not very protective in this cohort. In humans, it has been shown that ~10–20% of maternal cortisol can pass directly to the fetus, possibly due to bypassing the placental enzyme 11beta-HSD-2 (27). Therefore, it is possible that both of the glucocorticoids were able to cross the placental barrier, but cortisol may have been able to exert a greater effect on the fetus than dexamethasone. This outcome is unexpected, given that competitive binding analysis studies in the rat pancreas have shown that the glucocorticoid receptor binds synthetic dexamethasone with a higher affinity than corticosterone (65), and the former would not have been in competition for the mineralocorticoid receptor.

Recently, the multidrug resistance phosphoglycoprotein transporter has been shown to be highly expressed in the placenta, especially in early pregnancy as well as in other tissues (63). This transporter is able to transport glucocorticoids, including dexamethasone, back into maternal blood, thus reducing placental transfer to the fetus (66). If this transporter is present and active in the sheep placenta, it could reduce access of maternal dexamethasone to the fetal circulation and tissues, but presumably would act on cortisol as well. Alternatively, cortisol may be exerting some effects via the mineralocorticoid receptor. Finally, maternal betamethasone administered to sheep in late gestation alters metabolic and cardiovascular homeostasis in adult offspring, but appears to do so, at least in part, via indirect actions on the mother and the placenta (61).

These secondary effects of maternal glucocorticoid exposure may include maternal hyperglycemia and hyperinsulinemia, albeit of a short-term nature, however, which are known separately to impair glucose regulation and insulin secretion in adult offspring of rodents and humans (10, 26, 60, 62). Additionally, maternal glucocorticoids may also affect placental functional and vascular development. Thus maternal dexamethasone treatment restricts placental growth and labyrinthine vascular development (31).

In contrast to the effects on fasting glycemia and insulin secretion, neither dexamethasone nor cortisol treatment of pregnant sheep in early gestation altered whole body insulin sensitivity of glucose, FFAs, or amino acid uptake in adult male offspring. This is consistent with previous observations in female sheep aged 5 yr, where maternal dexamethasone in early pregnancy did not alter insulin sensitivity of glucose uptake (25). The present study did, however, show an increase in the disposition index for glucose metabolism following dexamethasone, but not cortisol, which is an index of insulin secretion in combination with sensitivity, while the disposition index for FFAs also tended to increase. This suggests that there may be increased insulin action on glucose and FFA metabolism, which is due primarily to increased insulin secretion, following maternal dexamethasone exposure in early gestation. This is also consistent with our laboratory's previous study where insulin sensitivity of the inhibition of lipolysis was increased in 5-yr-old female offspring exposed to dexamethasone in early gestation (25). As we proposed in that study, enhanced insulin sensitivity of FFAs, together with hyperinsulinemia, following maternal dexamethasone, might increase lipid storage and lead to increased adiposity in later life (25).

In conclusion, we have shown that maternal glucocorticoid exposure in early pregnancy in the sheep impairs fasting glycemia and alters insulin secretion and action, in a glucocorticoid-specific manner in adult male offspring. Maternal dexamethasone impairs fasting glycemia and increases first-phase insulin secretion, whereas maternal cortisol impairs fasting glycemia and increases second-phase insulin secretion, in male adult offspring. Dexamethasone did not have consistently greater effects than cortisol on metabolism and insulin action in offspring as hypothesized, suggesting other determinants of glucocorticoid action are present and that some consequences may be indirect results of effects on the placenta or mother. There appears to be a critical window during development at the end of the first month of gestation, whereby short exposure of the mother to either synthetic or natural glucocorticoids leads to hypertensive (shown previously, Refs. 16, 17) and hyperinsulinemic and hyperglycemic male offspring. Increased exposure to steroids in early gestation may, therefore, predispose offspring to the development of metabolic and cardiovascular disease with aging. Furthermore, males may be more susceptible than females to the effects of prenatal exposure to glucocorticoids (25) and, accordingly, have a greater risk in developing later adult disease.


   ACKNOWLEDGMENTS
 
The authors thank Andrew McAlinden for help with animal preparation and in vivo studies.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. A. Owens, Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, Univ. of Adelaide, Adelaide SA 5005, Australia (e-mail: julie.owens{at}adelaide.edu.au)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Andrews MH, Kostaki A, Setiawan E, McCabe L, Matthews SG. Developmental regulation of 5-HT1A receptor mRNA in the fetal limbic system: response to antenatal glucocorticoid. Dev Brain Res 149: 39–44, 2004.[CrossRef][Medline]
  2. Ashcroft FM, Harrison DE, Ashcroft SJ. Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312: 446–448, 1984.[CrossRef][Medline]
  3. Barbazanges A, Piazza PV, Le Moal M, Maccari S. Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. J Neurosci 16: 3943–3949, 1996.[Abstract/Free Full Text]
  4. Barg S, Olofsson CS, Schriever-Abeln J, Wendt A, Gebre-Medhin S, Renstrom E, Rorsman P. Delay between fusion pore opening and peptide release from large dense-core vesicles in neuroendocrine cells. Neuron 33: 287–299, 2002.[CrossRef][ISI][Medline]
  5. Barker DJ. The fetal and infant origins of adult disease. BMJ 301: 1111, 1990.[ISI][Medline]
  6. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet 341: 938–941, 1993.[CrossRef][ISI][Medline]
  7. Beitins IZ, Bayard F, Ances IG, Kowarski A, Migeon CJ. The metabolic clearance rate, blood production, interconversion and transplacental passage of cortisol and cortisone in pregnancy near term. Pediatr Res 7: 509–519, 1973.[ISI][Medline]
  8. Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CR. Glucocorticoid exposure in utero: new model for adult hypertension. Lancet 341: 339–341, 1993.[CrossRef][ISI][Medline]
  9. Bertram C, Trowern AR, Copin N, Jackson AA, Whorwood CB. The maternal diet during pregnancy programs altered expression of the glucocorticoid receptor and type 2 11beta-hydroxysteroid dehydrogenase: potential molecular mechanisms underlying the programming of hypertension in utero. Endocrinology 142: 2841–2853, 2001.[Abstract/Free Full Text]
  10. Bihoreau MT, Ktorza A, Kinebanyan MF, Picon L. Impaired glucose homeostasis in adult rats from hyperglycemic mothers. Diabetes 35: 979–984, 1986.[Abstract]
  11. Brown RW, Chapman KE, Kotelevtsev Y, Yau JL, Lindsay RS, Brett L, Leckie C, Murad P, Lyons V, Mullins JJ, Edwards CR, Seckl JR. Cloning and production of antisera to human placental 11beta-hydroxysteroid dehydrogenase type 2. Biochem J 313: 1007–1017, 1996.[ISI][Medline]
  12. Clifton VL, Murphy VE. Maternal asthma as a model for examining fetal sex-specific effects on maternal physiology and placental mechanisms that regulate human fetal growth. Placenta 25: S45–S52, 2004.[CrossRef][ISI][Medline]
  13. Cook DL, Hales CN. Intracellular ATP directly blocks K+ channels in pancreatic B-cells. Nature 311: 271–273, 1984.[CrossRef][Medline]
  14. de Rooij SR, Painter RC, Roseboom TJ, Phillips DIW, Osmond C, Barker DJP, Tanck MW, Michels RPJ, Bossuyt PMM, Bleker OP. Glucose tolerance at age 58 and the decline of glucose tolerance compared with age 50 in people prenatally exposed to the Dutch famine. Diabetologia 49: 637–643, 2006.[CrossRef][ISI][Medline]
  15. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol Endocrinol Metab Gastrointest Physiol 237: E214–E223, 1979.[Abstract/Free Full Text]
  16. Dodic M, Abouantoun T, O'Connor A, Wintour EM, Moritz KM. Programming effects of short prenatal exposure to dexamethasone in sheep. Hypertension 40: 729–734, 2002.[Abstract/Free Full Text]
  17. Dodic M, Hantzis V, Duncan J, Rees S, Koukoulas I, Johnson K, Wintour EM, Moritz K. Programming effects of short prenatal exposure to cortisol. FASEB J 16: 1017–1026, 2002.[Abstract/Free Full Text]
  18. Dodic M, May CN, Wintour EM, Coghlan JP. An early prenatal exposure to excess glucocorticoid leads to hypertensive offspring in sheep. Clin Sci (Lond) 94: 149–155, 1998.[Medline]
  19. Dodic M, McAlinden AT, Jefferies AJ, Wintour EM, Cock ML, May CN, Evans RG, Moritz KM. Differential effects of prenatal exposure to dexamethasone or cortisol on circulatory control mechanisms mediated by angiotensin II in the central nervous system of adult sheep. J Physiol 571: 651–660, 2006.[Abstract/Free Full Text]
  20. Drake AJ, Walker BR, Seckl JR. Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Comp Physiol 288: R34–R38, 2005.[Abstract/Free Full Text]
  21. Edwards CR, Benediktsson R, Lindsay RS, Seckl JR. Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension? Lancet 341: 355–357, 1993.[CrossRef][ISI][Medline]
  22. Evans PC, Ffolliott-Powell FM, Harding JE. A colorimetric assay for amino nitrogen in small volumes of blood: reaction with beta-naphthoquinone sulfonate. Anal Biochem 208: 334–337, 1993.[CrossRef][ISI][Medline]
  23. Flanagan DE, Moore VM, Godsland IF, Cockington RA, Robinson JS, Phillips DIW. Fetal growth and the physiological control of glucose tolerance in adults: a minimal model analysis. Am J Physiol Endocrinol Metab 278: E700–E706, 2000.[Abstract/Free Full Text]
  24. Gatford KL, De Blasio MJ, Thavaneswaran P, Robinson JS, McMillen IC, Owens JA. Postnatal ontogeny of glucose homeostasis and insulin action in sheep. Am J Physiol Endocrinol Metab 286: E1050–E1059, 2004.[Abstract/Free Full Text]
  25. Gatford KL, Wintour EM, De Blasio MJ, Owens JA, Dodic M. Differential timing for programming of glucose homoeostasis, sensitivity to insulin and blood pressure by in utero exposure to dexamethasone in sheep. Clin Sci (Lond) 98: 553–560, 2000.[Medline]
  26. Gauguier D, Bihoreau MT, Picon L, Ktorza A. Insulin secretion in adult rats after intrauterine exposure to mild hyperglycemia during late gestation. Diabetes 40: 109–114, 1991.[ISI][Medline]
  27. Gitau R, Cameron A, Fisk NM, Glover V. Fetal exposure to maternal cortisol. Lancet 352: 707–708, 1998.[CrossRef][ISI][Medline]
  28. Gurrin LC, Moss TJ, Sloboda DM, Hazelton ML, Challis JR, Newnham JP. Using WinBUGS to fit nonlinear mixed models with an application to pharmacokinetic modelling of insulin response to glucose challenge in sheep exposed antenatally to glucocorticoids. J Biopharm Stat 13: 117–139, 2003.[CrossRef][Medline]
  29. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303: 1019–1022, 1991.[ISI][Medline]
  30. Henquin J, Nenquin M, Stiernet P, Ahrén B. In vivo and in vitro glucose-induced biphasic insulin secretion in the mouse: pattern and role of cytoplasmic Ca2+ and amplification signals in beta-cells. Diabetes 55: 441–451, 2006.[Abstract/Free Full Text]
  31. Hewitt DP, Mark PJ, Waddell BJ. Glucocorticoids prevent the normal increase in placental vascular endothelial growth factor expression and placental vascularity during late pregnancy in the rat. Endocrinology 147: 5568–5574, 2006.[Abstract/Free Full Text]
  32. Hoenig M, Sharp GW. Glucose induces insulin release and a rise in cytosolic calcium concentration in a transplantable rat insulinoma. Endocrinology 119: 2502–2507, 1986.[Abstract]
  33. Holness MJ, Sugden MC. Dexamethasone during late gestation exacerbates peripheral insulin resistance and selectively targets glucose-sensitive functions in beta cell and liver. Endocrinology 142: 3742–3748, 2001.[Abstract/Free Full Text]
  34. Kauppila A, Ylikorkala O, Jarvinen PA, Haapalahti J. The function of the anterior pituitary-adrenal cortex axis in hyperemesis gravidarum. Br J Obstet Gynaecol 83: 11–16, 1976.[ISI][Medline]
  35. Kerzner LS, Stonestreet BS, Wu K, Sadowska G, Malee MP. Antenatal dexamethasone: effect on ovine placental 11beta-hydroxysteroid dehydrogenase type 2 expression and fetal growth. Pediatr Res 52: 706–712, 2002.[CrossRef][ISI][Medline]
  36. Kind KL, Clifton PM, Grant PA, Owens PC, Sohlstrom A, Roberts CT, Robinson JS, Owens JA. Effect of maternal feed restriction during pregnancy on glucose tolerance in the adult guinea pig. Am J Physiol Regul Integr Comp Physiol 284: R140–R152, 2003.[Abstract/Free Full Text]
  37. Lajic S, Nordenstrom A, Ritzen EM, Wedell A. Prenatal treatment of congenital adrenal hyperplasia. Eur J Endocrinol 151: U63–U69, 2004.[Abstract]
  38. Langley-Evans SC, Phillips GJ, Benediktsson R, Gardner DS, Edwards CR, Jackson AA, Seckl JR. Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta 17: 169–172, 1996.[ISI][Medline]
  39. Lesage J, Del-Favero F, Leonhardt M, Louvart H, Maccari S, Vieau D, Darnaudery M. Prenatal stress induces intrauterine growth restriction and programmes glucose intolerance and feeding behaviour disturbances in the aged rat. J Endocrinol 181: 291–296, 2004.[Abstract]
  40. Lindsay RS, Lindsay RM, Edwards CR, Seckl JR. Inhibition of 11-beta-hydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in the offspring. Hypertension 27: 1200–1204, 1996.[Abstract/Free Full Text]
  41. Lindsay RS, Lindsay RM, Waddell BJ, Seckl JR. Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone. Diabetologia 39: 1299–1305, 1996.[CrossRef][ISI][Medline]
  42. McMullen S, Osgerby JC, Thurston LM, Gadd TS, Wood PJ, Wathes DC, Michael AE. Alterations in placental 11 beta-hydroxysteroid dehydrogenase (11 betaHSD) activities and fetal cortisol:cortisone ratios induced by nutritional restriction prior to conception and at defined stages of gestation in ewes. Reproduction 127: 717–725, 2004.[Abstract/Free Full Text]
  43. Mercado AB, Wilson RC, Cheng KC, Wei JQ, New MI. Prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 80: 2014–2020, 1995.[Abstract]
  44. Moss TJM, Sloboda DM, Gurrin LC, Harding R, Challis JRG, Newnham JP. Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure. Am J Physiol Regul Integr Comp Physiol 281: R960–R970, 2001.[Abstract/Free Full Text]
  45. Nesher R, Cerasi E. Biphasic insulin release as the expression of combined inhibitory and potentiating effects of glucose. Endocrinology 121: 1017–1024, 1987.[Abstract]
  46. Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest 101: 2174–2181, 1998.[ISI][Medline]
  47. Ohara-Imaizumi M, Nagamatsu S. Insulin exocytotic mechanism by imaging technique. J Biochem (Tokyo) 140: 1–5, 2006.[Abstract/Free Full Text]
  48. Ohara-Imaizumi M, Nishiwaki C, Kikuta T, Nagai S, Nakamichi Y, Nagamatsu S. TIRF imaging of docking and fusion of single insulin granule motion in primary rat pancreatic beta-cells: different behaviour of granule motion between normal and Goto-Kakizaki diabetic rat beta-cells. Biochem J 381: 13–18, 2004.[CrossRef][ISI][Medline]
  49. Pacini G. The hyperbolic equilibrium between insulin sensitivity and secretion. Nutr Metab Cardiovasc Dis 16, Suppl 1: S22–S27, 2006.[CrossRef][ISI][Medline]
  50. Painter RC, Roseboom TJ, Bleker OP. Prenatal exposure to the Dutch famine and disease in later life: An overview. Reprod Toxicol 20: 345–352, 2005.[CrossRef][ISI][Medline]
  51. Parker L, Lamont DW, Unwin N, Pearce MS, Bennett SM, Dickinson HO, White M, Mathers JC, Alberti KG, Craft AW. A lifecourse study of risk for hyperinsulinaemia, dyslipidaemia and obesity (the central metabolic syndrome) at age 49–51 years. Diabet Med 20: 406–415, 2003.[CrossRef][ISI][Medline]
  52. Ravelli AC, van der Meulen JH, Michels RP, Osmond C, Barker DJ, Hales CN, Bleker OP. Glucose tolerance in adults after prenatal exposure to famine. Lancet 351: 173–177, 1998.[CrossRef][ISI][Medline]
  53. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Bleker OP. Plasma lipid profiles in adults after prenatal exposure to the Dutch famine. Am J Clin Nutr 72: 1101–1106, 2000.[Abstract/Free Full Text]
  54. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Schroeder-Tanka JM, van Montfrans GA, Michels RP, Bleker OP. Coronary heart disease after prenatal exposure to the Dutch famine, 1944–45. Heart 84: 595–598, 2000.[Abstract/Free Full Text]
  55. Roseboom TJ, Van der Meulen JH, Ravelli AC, Osmond C, Barker DJ, Bleker OP. Plasma fibrinogen and factor VII concentrations in adults after prenatal exposure to famine. Br J Haematol 111: 112–117, 2000.[CrossRef][ISI][Medline]
  56. Roseboom TJ, van der Meulen JH, Ravelli AC, van Montfrans GA, Osmond C, Barker DJ, Bleker OP. Blood pressure in adults after prenatal exposure to famine. J Hypertens 17: 325–330, 1999.[CrossRef][ISI][Medline]
  57. Seckl JR. Glucocorticoids, feto-placental 11-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids 62: 89–94, 1997.[CrossRef][ISI][Medline]
  58. Seckl JR. Prenatal glucocorticoids and long-term programming. Eur J Endocrinol 151: U49–U62, 2004.[Abstract]
  59. Siebe H, Baude G, Lichtenstein I, Wang D, Buhler H, Hoyer GA, Hierholzer K. Metabolism of dexamethasone: sites and activity in mammalian tissues. Renal Physiol Biochem 16: 79–88, 1993.[ISI][Medline]
  60. Singh R, Pearson E, Avery PJ, McCarthy MI, Levy JC, Hitman GA, Sampson M, Walker M, Hattersley AT. Reduced beta cell function in offspring of mothers with young-onset type 2 diabetes. Diabetologia 49: 1876–1880, 2006.[CrossRef][ISI][Medline]
  61. Sloboda DM, Moss TJM, Li S, Doherty DA, Nitsos I, Challis JRG, Newnham JP. Hepatic glucose regulation and metabolism in adult sheep: effects of prenatal betamethasone. Am J Physiol Endocrinol Metab 289: E721–E728, 2005.[Abstract/Free Full Text]
  62. Sobngwi E, Boudou P, Mauvais-Jarvis F, Leblanc H, Velho G, Vexiau P, Porcher R, Hadjadj S, Pratley R, Tataranni PA, Calvo F, Gautier JF. Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet 361: 1861–1865, 2003.[CrossRef][ISI][Medline]
  63. Stein WD. Kinetics of the multidrug transporter (P-glycoprotein) and its reversal. Physiol Rev 77: 545–590, 1997.[Abstract/Free Full Text]
  64. Sugden MC, Holness MJ. Gender-specific programming of insulin secretion and action. J Endocrinol 175: 757–767, 2002.[Abstract]
  65. Svec F, Rudis M. Glucocorticoid hormone receptors in rat pancreas. Biochim Biophys Acta 674: 30–36, 1981.[Medline]
  66. Ueda K, Okamura N, Hirai M, Tanigawara Y, Saeki T, Kioka N, Komano T, Hori R. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem 267: 24248–24252, 1992.[Abstract/Free Full Text]
  67. Unsel N, Benian A, Erel CT. Leptin levels in women with hyperemesis gravidarum. Int J Gynaecol Obstet 84: 162–163, 2004.[CrossRef][Medline]
  68. van Os J, Selten JP. Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. Br J Psychiatry 172: 324–326, 1998.[Abstract/Free Full Text]
  69. Viluksela M, Unkila M, Pohjanvirta R, Tuomisto JT, Stahl BU, Rozman KK, Tuomisto J. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on liver phosphoenolpyruvate carboxykinase (PEPCK) activity, glucose homeostasis and plasma amino acid concentrations in the most TCDD-susceptible and the most TCDD-resistant rat strains. Arch Toxicol 73: 323–326, 1999.[CrossRef][ISI][Medline]
  70. Whorwood CB, Firth KM, Budge H, Symonds ME. Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11beta-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin II receptor in neonatal sheep. Endocrinology 142: 2854–2864, 2001.[Abstract/Free Full Text]
  71. Wollheim CB, Sharp GW. Regulation of insulin release by calcium. Physiol Rev 61: 914–973, 1981.[Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
K. L. Gatford, J. A. Owens, S. Li, T. J. M. Moss, J. P. Newnham, J. R. G. Challis, and D. M. Sloboda
Repeated betamethasone treatment of pregnant sheep programs persistent reductions in circulating IGF-I and IGF-binding proteins in progeny
Am J Physiol Endocrinol Metab, July 1, 2008; 295(1): E170 - E178.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
S. L. Wakefield, M. Lane, S. J. Schulz, M. L. Hebart, J. G. Thompson, and M. Mitchell
Maternal supply of omega-3 polyunsaturated fatty acids alter mechanisms involved in oocyte and early embryo development in the mouse
Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E425 - E434.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
293/1/E75    most recent
00689.2006v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (2)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by De Blasio, M. J.
Right arrow Articles by Owens, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by De Blasio, M. J.
Right arrow Articles by Owens, J. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS