1 Institut National de la Santé et de la Recherche Médicale Unité 457, Hôpital Robert Debré, Paris; and 2 Unité Propre de Recherche de l'Enseignement Superieur Equipe d'Accueil, EA 2701, University of Lille 1, Lille, France
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In
rats, poor fetal growth due to maternal food restriction during
pregnancy is associated with decreased -cell mass at birth and
glucose intolerance in adulthood. Overexposure to glucocorticoids in
utero can induce intrauterine growth retardation in humans and animals
and subsequent glucose intolerance in rodents. The aims of this study
were to investigate whether glucocorticoid overexposure mediates the
effect of undernutrition on
-cell mass and to study their potential
role in normally nourished rats. Undernutrition significantly increased
maternal and fetal corticosterone levels. Twenty-one-day-old fetuses
with undernutrition showed growth retardation and decreased pancreatic
insulin content; adrenalectomy and subcutaneous corticosterone implants
in their dams prevented the maternal corticosterone increase and
restored fetal
-cell mass. In fetuses with normal nutrition, fetal
corticosterone levels were negatively correlated to fetal weight and
insulin content; fetal
-cell mass increased from 355 ± 48 µg
in sham to 516 ± 160 µg after maternal adrenalectomy;
inhibition of steroid production by metyrapone induced a further
increase to 757 ± 125 µg. Our data support the new concept of a
negative role of glucocorticoids in fetal
-cell development.
undernutrition; pancreatic -cell; morphometry; fetal
environment
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
DURING THE LAST DECADE, the possibility that fetal events may influence the risk of disease in adulthood has generated considerable interest. Epidemiological studies published in the early 1990s suggest strong links between fetal growth and the occurrence of degenerative diseases later in life. Individuals who were thin at birth are at increased risk for cardiovascular disease (including hypertension) and glucose intolerance or type 2 diabetes in adulthood (2, 18, 23, 34, 40). Intrauterine growth retardation (IUGR) is thus a risk factor for glucose intolerance, hypertension, and dyslipidemia, a combination called "syndrome X." From these epidemiological findings, the idea of fetal programming, the process whereby a factor at a critical or sensitive window of development exerts effects that persist throughout life, has been advanced (3).
The detailed mechanisms by which fetal undernutrition increases the
risk of syndrome X are not perfectly understood. Besides insulin
resistance, which has been proposed to occur in response to
undernutrition (32), a primary defect in fetal -cell
development has also been suggested (17). This exciting
hypothesis proposes that poor nutrition in utero, at a time when
-cell development proceeds more rapidly, reduces this development
and thereby the number of available
-cells later in life. Because
the latter hypothesis cannot be investigated easily in clinical
settings, animal models have been developed. We recently designed a rat model of undernutrition involving an overall reduction in maternal food
intake during the last week of pregnancy and throughout lactation (13). In this model, fetuses with growth retardation have
a decrease in pancreatic
-cell mass (8), which persists
into adulthood (9) and ultimately causes glucose
intolerance (10, 11). These findings support a role for
intrauterine nutrition in programming
-cell development.
Another situation characterized by IUGR and subsequent glucose
intolerance is fetal overexposure to glucocorticoids. Studies in humans
(36) and rodents (31) have shown that
maternal glucocorticoid administration during pregnancy can induce
IUGR. During normal pregnancy in rats, the fetuses are protected
against maternal corticosterone by a placental enzyme,
11-hydroxysteroid dehydrogenase type 2, which converts
corticosterone to an inactive compound (6, 29). Inhibition
of this enzyme by carbenoxolone is associated with decreased weight at
birth and with glucose intolerance in adulthood (22).
Similarly, administration to pregnant rats of the 11
-hydroxysteroid
dehydrogenase type 2-resistant synthetic glucocorticoid dexamethasone
induces IUGR and programs permanent hyperglycemia and increased blood
pressure in the adult offspring (30). An experimental
study in rats showed that the hypertension observed in adults whose
dams were fed a low-protein diet during pregnancy could be prevented by
chemical blockade of maternal corticosterone production
(21), suggesting that the link between maternal protein
deprivation and adult-onset hypertension may be mediated by maternal
glucocorticoids. In aggregate, these data support the possibility that
the hypothalamo-pituitary-adrenal axis may play a role in programming
the adult-onset metabolic consequences of fetal undernutrition
(9, 21, 30, 33, 37).
Because maternal undernutrition and fetal overexposure to
glucocorticoids lead to glucose intolerance in adulthood, a legitimate question is whether the negative effects of these two abnormalities on
fetal -cell development are linked. The present study investigated the effects of glucocorticoids on
-cell development under normal conditions and during fetal undernutrition. In normal fetuses, correlations linking fetal corticosterone to fetal weight and insulin
content were evaluated. In fetuses of dams with food deprivation or
decreased circulating corticosterone levels, correlations between maternal or fetal corticosterone levels and fetal
-cell mass were
investigated. The results strongly support the new concept of a
negative role of glucocorticoids in fetal
-cell development.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Animals and Study Design
Animals. Female Wistar rats (200 g; Janvier Breeding Center, Le Genêt-St-Isle, France) were exposed to a 12:12-h (0700-1900) light-dark cycle and constant temperature (22°C). They had free access to water and were fed standard laboratory rat chow (22% protein, 5% fat, 53% carbohydrates; no. 113, UAR, Villemoisson sur Orge, France). The female rats were mated, and day 0 of pregnancy was defined as the day on which a vaginal plug was expelled. The two laboratories where the study was conducted are accredited by the French Ministry of Agriculture to conduct experiments in laboratory animals (accreditation numbers 7612 and 4860).
Food restriction. Maternal undernutrition was achieved as described previously (12). Briefly, the dams were fed 50% of the daily ad libitum intake (i.e., 12 g/day) from day 14 to day 21 of pregnancy. Control dams were fed ad libitum. All animals were fed every day at 1800.
To determine the effect of undernutrition on maternal corticosterone levels, blood samples were collected on days 15, 17, and 19 of pregnancy (between 1000 and 1200) from the tail vein in tubes containing 5% EDTA. After centrifugation, the plasma was separated and stored atAdrenalectomy and corticosterone replacement treatment.
Adrenalectomy or a sham operation (n = 8-10
dams/group) was performed under light anesthesia on day 13 of pregnancy. Each adrenalectomized dam received a subcutaneous implant
containing 100 mg of corticosterone (mixed in equal parts with
cholesterol) to maintain basal levels of corticosterone (ADX-Cort
group) (28). To compensate for the absence of aldosterone,
0.9% NaCl was added to their drinking water. On day 14 of
pregnancy, the ADX-Cort and sham-operated dams were given a 50%
restricted diet or fed ad libitum until day 21 of pregnancy.
The four groups of animals are designated as follows: sham-operated
dams fed ad libitum (Sham-C), sham-operated dams fed a 50% restricted
diet (Sham-R), adrenalectomized dams implanted with a corticosterone
pellet and fed ad libitum (ADX-Cort-C), and adrenalectomized dams
implanted with a corticosterone pellet and fed a 50% restricted diet
(ADX-Cort-R, n = 4 dams/group). On day 21 of
pregnancy, the dams were killed by decapitation. Fetuses
(n = 10-12/litter) were collected by cesarean
section, weighed, and immediately killed by decapitation. Blood samples were processed for corticosterone determination as described above, and
the fetal pancreases were dissected and fixed for immunohistochemistry. This experimental protocol was used to investigate the impact of
corticosterone overexposure on the alteration of fetal -cell mass
observed during undernutrition.
Metyrapone treatment.
Another means of investigating the role of glucocorticoids on fetal
-cell development is exposure of the fetuses to low circulating corticosterone levels while the dams are fed a normal diet. In this
study, a decrease in corticosterone levels was obtained by performing
maternal adrenalectomy on day 14 of pregnancy (ADX group) or
by combining this procedure with administration of metyrapone (ADX-Mety
group). Metyrapone, which crosses the placental barrier and inhibits
fetal steroid production (1), was injected subcutaneously into the dams at a dose of 25 mg (dissolved in 200 µl of 0.9% NaCl)
twice daily (0900 and 1900) from day 16 to day 21 of pregnancy. The ADX dams received injections of the vehicle alone.
The fetuses were collected on day 21 of pregnancy, and their
pancreases were excised. Inasmuch as fetal rats do not produce
corticosterone until day 16 (8), metyrapone
treatment was not given before this time. Cross-reactivity of the
anti-corticosterone antibody with 11-deoxycorticosterone, which
accumulates during metyrapone treatment, did not allow the measurements
of fetal corticosterone levels; however, the twofold increase in fetal
adrenal weight compared with that of fetuses from sham-operated dams
indicated the efficiency of the adrenal blockade.
Correlations linking fetal corticosterone, body weight, and insulin content on day 21. To look for correlations between fetal corticosterone levels and fetal insulin contents or fetal weight, fetuses (n = 23) from three dams fed a normal diet were studied on day 21 of pregnancy. Fetal weight, corticosterone levels, and pancreatic insulin content were determined in each fetus.
Tissue Processing
Fixation and processing for immunohistochemistry. For immunohistochemical studies, the pancreases were fixed in a 3.7% formalin solution, dehydrated in 100% ethanol and 100% toluene using an automatic tissue processor (model TP1020, Leica, Rueil Malmaison, France), and embedded in paraffin using the Paraffin-Embedding Center (model EG 1160, Leica). A rotary microtome (model RM 2145, Leica) was used to cut the entire pancreases into 6-µm-thick sections, which were collected on gelatin-coated slides. The slides were left at 37°C overnight and then stored at 4°C until they were processed for immunohistochemical studies.
Morphometry measurements.
-Cells were detected using a polyclonal guinea pig anti-insulin
antibody (Dako, Trappes, France) revealed by incubation with an
alkaline phosphatase-conjugated anti-rabbit antibody and stained blue
by nitro blue tetrazolium (Vector, Biosys, Compiègne, France). The
-cell fraction was measured using a Leica DMRB microscope equipped with a color videocamera coupled to a Quantimet 500MC computer
(screen magnification ×24), as described previously (12). Briefly, the
-cell fraction was measured as the ratio of the insulin-positive cell area to the total tissue area on the entire section. Five sections taken at 150-µm intervals throughout the pancreas were analyzed from five fetuses in each group. The
-cell mass was obtained by multiplying the
-cell fraction by the weight of
the pancreas. The number of islets (defined as insulin-positive aggregates
25 µm diameter) per square centimeter was determined.
Insulin content determination.
After sonication of the pancreases in 4 ml of cold acidified ethyl
alcohol (1.5% HCl-75% ethyl alcohol), the insulin was extracted overnight at 20°C and the pancreatic remnants were centrifuged. The
supernatant was kept at
20°C until use.
Hormone Assays
Corticosterone assay. Plasma corticosterone was assayed after delipidation in isooctane followed by extraction in ethyl acetate. Experiments with known amounts of corticosterone showed that recovery exceeded 95%. Corticosterone levels were determined using an RIA with a highly specific corticosterone antiserum (UCB Bioproducts), as previously described (5). The detection threshold was 1 ng/ml. The intra- and interassay variations were 2.4 and 4.4%, respectively.
Insulin assay. Immunoreactive insulin was measured using an RIA with monoiodized 125I-labeled porcine insulin (Sorin Biomedica, Salligia, Italy) as the tracer, guinea pig anti-insulin antibody (kindly provided by Dr. Van Schravendijk, Brussels, Belgium), and purified rat insulin (Novo, Boulogne, France) as the standard. Charcoal was used to separate free from bound hormone. The sensitivity of the assay was 0.25 ng/ml (6 µU/ml).
Statistical Analysis
Values are means ± SD. Statistical analysis was performed using multiple analysis of variance followed by Fisher's protected least significant difference post hoc test. Unpaired Student's t-test was also used when appropriate. Correlations between variables were studied by standard linear regression and confirmed by the nonparametric Spearman's rank correlation coefficient (Spearman's ![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Body Weight and Pancreatic Insulin Content Were Negatively Correlated With Corticosterone in 21- Day-Old Fetuses of Dams Fed a Normal Diet
Linear regression analysis showed that fetal weight and pancreatic insulin content were negatively correlated to fetal corticosterone levels [r2 = 0.323, P = 0.005 (Fig. 1A) and r2 = 0.190, P = 0.03 (Fig. 1B), respectively]. There was also a significant rank correlation when the data were analyzed using the nonparametric Spearman's
|
Effects of Undernutrition
In the pregnant control dams, corticosterone levels were significantly higher on day 21 than earlier in the pregnancy (P < 0.01; Fig. 2), in keeping with previous data (10). However, corticosterone levels on days 19 and 21 were significantly increased in the food-restricted pregnant dams compared with the control dams (P < 0.01 on day 19 and P < 0.05 on day 21; Fig. 2).
|
In the fetuses from food-restricted dams, corticosterone levels were
elevated by 30% (P < 0.001; Table
1). Fetal adrenal weight was reduced,
indicating that the fetal corticosterone increase was due, at least in
part, to maternal corticosterone overproduction (Table 1). In addition,
21-day-old fetuses from food-restricted dams had significant decreases
in body weight (P < 0.001) and pancreatic weight
(P < 0.01) compared with fetuses of control dams
(Table 1). Total insulin content per pancreas and relative insulin
content per gram of body weight were decreased by one-half in these
fetuses (P < 0.001; Table 1).
|
Normalization of Maternal Corticosterone Restored -Cell Mass in
the Fetuses With Undernutrition
|
|
-Cell Mass in Fetuses From ADX Females Given Metyrapone
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The present study was designed to investigate the effects of
glucocorticoids on fetal -cell development and to determine whether
overexposure to glucocorticoids contributes to the decrease in
-cell
mass observed during fetal undernutrition. Our results make a strong
case for a key role of corticosterone in
-cell development. In
animals with normal nutrition, pancreatic insulin content was
negatively correlated to corticosterone levels, and
-cell mass
increased when fetal steroid production was impaired. In fetuses with
undernutrition, in contrast,
-cell mass was decreased and
corticosterone levels increased.
Glucocorticoid overexposure during pregnancy has been reported to cause
IUGR in humans (36) and animals (4), as well as glucose intolerance later in life in rodents (30). We
tested the hypothesis that glucocorticoids may affect fetal -cell
development, not only in fetuses with normal nutrition, but also in
fetuses with IUGR. In fetuses with normal nutrition, we found a
negative correlation between fetal corticosterone levels and fetal
weight. Similarly, increased cortisol levels have been reported in
human neonates with IUGR (7, 11, 14). Our finding that
insulin content was correlated with corticosterone levels but not with fetal weight in normal rat fetuses suggests that insulin content may be
more heavily dependent on glucocorticoid exposure than on nutritional
status. The negative correlation between fetal corticosterone and
insulin content in our study supports a negative effect of
glucocorticoids on
-cell development. In an earlier study
(11), we found that glucose intolerance occurred as a result of a primary defect in
-cell development in a rat model of
perinatal undernutrition, and we hypothesized that this defect might be
due to glucocorticoid overexposure in utero. The present study showed
clearly that maternal food restriction increased maternal and fetal
corticosterone levels and decreased fetal pancreatic insulin content
and
-cell mass. Preventing the corticosterone increase in the
food-restricted dams restored the fetal
-cell mass. Thus food
restriction caused the corticosterone elevation, which in turn caused
the
-cell mass decrease. Interestingly, restoration of the fetal
-cell mass was associated with correction of the decrease in the
islet number per square centimeter, the main neonatal abnormality
induced by undernutrition in this rat model (12). Although
-cell proliferation was not measured in fetuses at 21 days
gestation, the fact that it was not decreased at birth (i.e.,
12 h later) in undernourished neonates does not favor this
hypothesis (12). Besides, the corticosterone elevation or
normalization observed during malnutrition was not associated with a
different
-cell size. On the other hand, increased apoptosis might contribute to the decreased
-cell mass observed during overexposure to glucocorticoids. Indeed, it has been shown recently by
Weinhaus and co-workers (41) that dexamethasone inhibited the islet cell proliferation induced by prolactin while increasing apoptosis. Whether similar alterations of
-cell
proliferation and/or apoptosis occur in utero during
overexposure to glucocorticoids deserves further investigations.
The observation that pancreatic weight was not restored in fetuses from
food-restricted dams with normalized corticosterone levels suggested in
the pancreas a more specific and negative role of corticosteroids on
the -cells. To confirm these results, we studied the effects of
fetal glucocorticoid underexposure on
-cell mass in normal rats. To
reduce fetal corticosterone levels to a very low level, adrenalectomy
was performed in the dams and followed by administration of metyrapone,
a drug that inhibits fetal steroid production (1). In the
fetuses,
-cell mass increased twofold compared with the controls.
Increases in mean islet size and islet number per square centimeter
were noted also. Thus glucocorticoid underexposure may promote islet
neogenesis, whereas overexposure may have the opposite effect. The
increase in islet size in the fetuses with glucocorticoid underexposure
may reflect increased
-cell proliferation and/or
-cell
hypertrophy. Taken together, our experiments demonstrate that
-cells
do develop during the time window investigated in our study and that
this development is sensitive to glucocorticoids. Whether
glucocorticoids play a similar role earlier in fetal life remains to be
determined. There is some evidence that maternal glucocorticoids may be
required to maintain early
-cell development between days
12 and 15 of pregnancy (20).
The mechanisms by which glucocorticoids modulate -cell development
deserve further investigation. Whether glucocorticoids affect
-cells
directly or influence the differentiation of precursor cells into
exocrine or endocrine cells remains to be determined. Several studies
suggest a direct effect of glucocorticoids on
-cells. It has been
shown that
-cells express the glucocorticoid receptor
(26) as early as day 13 in rat fetuses
(19, 20). The identification of a negative glucocorticoid
response element in the human insulin promoter (15),
together with reports of decreased insulin or GLUT-2 mRNA levels in
-cell lines or adult islets exposed to dexamethasone (16, 38,
41), also supports a direct effect of glucocorticoids on
-cells. Alternatively, glucocorticoids may influence the development
or the maturation of the exocrine pancreas. Positive regulation of the
mouse amylase gene by glucocorticoids through a glucose response
element has been reported (39). The AR42J cell line, which
shares the multipotency of pancreatic precursor cells, has been shown
to differentiate into acinar cells in vitro when exposed to
dexamethasone (24) and into insulin-secreting cells when
exposed to activin and
-cellulin (25). Moreover, early
in vitro studies demonstrated that glucocorticoids inhibited insulin
content and islet mass in cultured explants while enhancing the
accumulation of exocrine enzymes and the acinar mass (27,
35). Taken together, these data suggest that glucocorticoids may
favor development of the exocrine pancreas and inhibit development of
the endocrine pancreas, possibly by guiding pancreatic precursor cells
toward the exocrine differentiation pathway.
Experimental studies in animals have documented many examples of fetal
programming of chronic degenerative diseases. Several showed that the
development of hypertension in adults is linked to alterations in
glucocorticoid levels during fetal life (37). Another
study demonstrated that treatment of pregnant rats with dexamethasone
induced glucose intolerance later in life in the offspring.
Associations have been reported between these disorders and increased
hepatic expression of the glucocorticoid receptor and of
phosphoenolpyruvate carboxykinase (30). To our
knowledge, the present work is the first evidence of a link between
fetal glucocorticoid levels and -cell development in vivo. Its
results, together with the previously demonstrated association of early alterations in
-cell development with glucose intolerance later in
life, support the concept that glucose intolerance in adulthood is
programmed by glucocorticoid-induced alterations in fetal
-cell development.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Belinda Duchene for excellent technical assistance.
![]() |
FOOTNOTES |
---|
This work was funded by the Institut National de la Santé et de la Recherche Médicale. B. Blondeau has been awarded a doctoral fellowship by the Ministère de l'Education Nationale, de la Recherche, et de la Technologie.
Address for reprint requests and other correspondence: B. Bréant, INSERM U 457, Hôpital Robert Debré, 48 boulevard Sérurier, 75019 Paris, France (E-mail: breant{at}idf.inserm.fr).
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.
Received 20 March 2001; accepted in final form 4 April 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Baram, TZ,
and
Schultz L.
Fetal and maternal levels of corticosterone and ACTH after pharmacological adrenalectomy.
Life Sci
47:
485-489,
1990[ISI][Medline]. [Corrigenda. Life Sci 47: 1071, 1990.]
2.
Barker, DJ,
Gluckman PD,
Godfrey KM,
Harding JE,
Owens JA,
and
Robinson JS.
Fetal nutrition and cardiovascular disease in adult life.
Lancet
341:
938-941,
1993[ISI][Medline].
3.
Barker, DJP
Fetal origins of coronary heart disease.
Br Med J
311:
171-174,
1995
4.
Benediktsson, R,
Lindsay RS,
Noble J,
Seckl JR,
and
Edwards CR.
Glucocorticoid exposure in utero: new model for adult hypertension.
Lancet
341:
339-341,
1993[ISI][Medline]. [Corrigenda. Lancet 341: 27 February 1993, p. 572]
5.
Bernet, F,
Bernard J,
Laborie C,
Montel V,
Maubert E,
and
Dupouy JP.
Neuropeptide Y (NPY)- and vasoactive intestinal peptide (VIP)-induced aldosterone secretion by rat capsule/glomerular zone could be mediated by catecholamines via 1-adrenergic receptors.
Neurosci Lett
166:
109-112,
1994[ISI][Medline].
6.
Brown, RW,
Diaz R,
Robson AC,
Kotelevtsev YV,
Mullins JJ,
Kaufman MH,
and
Seckl JR.
The ontogeny of 11-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development.
Endocrinology
137:
794-797,
1996[Abstract].
7.
Clark, PM,
Hindmarsh PC,
Shiell AW,
Law CM,
Honour JW,
and
Barker DJ.
Size at birth and adrenocortical function in childhood.
Clin Endocrinol (Oxf)
45:
721-726,
1996[ISI][Medline].
8.
Cohen, A.
Plasma corticosterone concentration in the foetal rat.
Horm Metab Res
5:
66,
1973[ISI][Medline].
9.
Dodic, M,
Peers A,
Coghlan JP,
and
Wintour M.
Can excess glucocorticoid predispose to cardiovascular and metabolic disease in middle age?
Trends Endocrinol Metab
10:
86-91,
1999[ISI][Medline].
10.
Dupouy, JP,
Coffigny H,
and
Magre S.
Maternal and foetal corticosterone levels during late pregnancy in rats.
J Endocrinol
65:
347-352,
1975[Abstract].
11.
Economides, DL,
Nicolaides KH,
Linton EA,
Perry LA,
and
Chard T.
Plasma cortisol and adrenocorticotropin in appropriate and small for gestational age fetuses.
Fetal Ther
3:
158-164,
1988[Medline].
12.
Garofano, A,
Czernichow P,
and
Breant B.
In utero undernutrition impairs rat -cell development.
Diabetologia
40:
1231-1234,
1997[ISI][Medline].
13.
Garofano, A,
Czernichow P,
and
Breant B.
Postnatal somatic growth and insulin contents in moderate or severe intrauterine growth retardation in the rat.
Biol Neonate
73:
89-98,
1998[ISI][Medline].
14.
Goland, RS,
Jozak S,
Warren WB,
Conwell IM,
Stark RI,
and
Tropper PJ.
Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses.
J Clin Endocrinol Metab
77:
1174-1179,
1993[Abstract].
15.
Goodman, PA,
Medina-Martinez O,
and
Fernandez-Mejia C.
Identification of the human insulin negative regulatory element as a negative glucocorticoid response element.
Mol Cell Endocrinol
120:
139-146,
1996[ISI][Medline].
16.
Gremlich, S,
Roduit R,
and
Thorens B.
Dexamethasone induces posttranslational degradation of GLUT2 and inhibition of insulin secretion in isolated pancreatic -cells. Comparison with the effects of fatty acids.
J Biol Chem
272:
3216-3222,
1997
17.
Hales, CN,
and
Barker DJ.
Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis.
Diabetologia
35:
595-601,
1992[ISI][Medline].
18.
Hales, CN,
Barker DJ,
Clark PM,
Cox LJ,
Fall C,
Osmond C,
and
Winter PD.
Fetal and infant growth and impaired glucose tolerance at age 64.
Br Med J
303:
1019-1022,
1991[ISI][Medline].
19.
Kitraki, E,
Kittas C,
and
Stylianopoulou F.
Glucocorticoid receptor gene expression during rat embryogenesis. An in situ hybridization study.
Differentiation
62:
21-31,
1997[ISI][Medline].
20.
Komatsu, S,
Yamamoto M,
Arishima K,
and
Eguchi Y.
Maternal adrenocortical hormones maintain the early development of pancreatic B cells in the fetal rat.
J Anat
193:
551-557,
1998[ISI][Medline].
21.
Langley-Evans, SC.
Intrauterine programming of hypertension by glucocorticoids.
Life Sci
60:
1213-1221,
1997[ISI][Medline].
22.
Lindsay, RS,
Lindsay RM,
Waddell BJ,
and
Seckl JR.
Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11-hydroxysteroid dehydrogenase inhibitor carbenoxolone.
Diabetologia
39:
1299-1305,
1996[ISI][Medline].
23.
Lithell, HO,
McKeigue PM,
Berglund L,
Mohsen R,
Lithell UB,
and
Leon DA.
Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years.
Br Med J
312:
406-410,
1996
24.
Logsdon, CD,
Moessner J,
Williams JA,
and
Goldfine ID.
Glucocorticoids increase amylase mRNA levels, secretory organelles, and secretion in pancreatic acinar AR42J cells.
J Cell Biol
100:
1200-1208,
1985[Abstract].
25.
Mashima, H,
Ohnishi H,
Wakabayashi K,
Mine T,
Miyagawa J,
Hanafusa T,
Seno M,
Yamada H,
and
Kojima I.
-Cellulin and activin A coordinately convert amylase-secreting pancreatic AR42J cells into insulin-secreting cells.
J Clin Invest
97:
1647-1654,
1996
26.
Matthes, H,
Kaiser A,
Stier U,
Riecken EO,
and
Rosewicz S.
Glucocorticoid receptor gene expression in the exocrine and endocrine rat pancreas.
Endocrinology
135:
476-479,
1994[Abstract].
27.
McEvoy, RC,
and
Hegre OD.
Foetal rat pancreas in organ culture: effects of media supplementation with various steroid hormones on the acinar and islet components.
Differentiation
6:
105-111,
1976[ISI][Medline].
28.
Meyer, JS,
Micco DJ,
Stephenson BS,
Krey LC,
and
McEwen BS.
Subcutaneous implantation method for chronic glucocorticoid replacement therapy.
Physiol Behav
22:
867-870,
1979[ISI][Medline].
29.
Murphy, BE,
Clark SJ,
Donald IR,
Pinsky M,
and
Vedady D.
Conversion of maternal cortisol to cortisone during placental transfer to the human fetus.
Am J Obstet Gynecol
118:
538-541,
1974[ISI][Medline].
30.
Nyirenda, MJ,
Lindsay RS,
Kenyon CJ,
Burchell A,
and
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
31.
Nyirenda, MJ,
and
Seckl JR.
Intrauterine events and the programming of adulthood disease: the role of fetal glucocorticoid exposure.
Int J Mol Med
2:
607-614,
1998[ISI][Medline].
32.
Phillips, DI.
Insulin resistance as a programmed response to fetal undernutrition.
Diabetologia
39:
1119-1122,
1996[ISI][Medline].
33.
Phillips, DI,
Barker DJ,
Fall CH,
Seckl JR,
Whorwood CB,
Wood PJ,
and
Walker BR.
Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome?
J Clin Endocrinol Metab
83:
757-760,
1998
34.
Phipps, K,
Barker DJ,
Hales CN,
Fall CH,
Osmond C,
and
Clark PM.
Fetal growth and impaired glucose tolerance in men and women.
Diabetologia
36:
225-228,
1993[ISI][Medline].
35.
Rall, L,
Pictet R,
Githens S,
and
Rutter WJ.
Glucocorticoids modulate the in vitro development of the embryonic rat pancreas.
J Cell Biol
75:
398-409,
1977[Abstract].
36.
Reinisch, JM,
Simon NG,
Karow WG,
and
Gandelman R.
Prenatal exposure to prednisone in humans and animals retards intrauterine growth.
Science
202:
436-438,
1978[ISI][Medline].
37.
Seckl, JR.
Glucocorticoids, feto-placental 11-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease.
Steroids
62:
89-94,
1997[ISI][Medline].
38.
Sharma, S,
Jhala US,
Johnson T,
Ferreri K,
Leonard J,
and
Montminy M.
Hormonal regulation of an islet-specific enhancer in the pancreatic homeobox gene STF-1.
Mol Cell Biol
17:
2598-2604,
1997[Abstract].
39.
Slater, EP,
Hesse H,
Muller JM,
and
Beato M.
Glucocorticoid receptor binding site in the mouse -amylase 2 gene mediates response to the hormone.
Mol Endocrinol
7:
907-914,
1993[Abstract].
40.
Valdez, R,
Athens MA,
Thompson GH,
Bradshaw BS,
and
Stern MP.
Birthweight and adult health outcomes in a biethnic population in the USA.
Diabetologia
37:
624-631,
1994[ISI][Medline].
41.
Weinhaus, AJ,
Bhagroo NV,
Brelje TC,
and
Sorenson RL.
Dexamethasone counteracts the effect of prolactin on islet function: implications for islet regulation in late pregnancy.
Endocrinology
141:
1384-1393,
2000