Effect of fetal dexamethasone exposure on the development of adult insulin sensitivity in a rat model.
OBJECTIVE
A rat model was designed to determine if fetal dexamethasone exposure is associated with decreased insulin sensitivity in adulthood, manifested as decreased binding of p85 to phosphorylated insulin receptor substrate-1 (IRS-1) within the phosphatidylinositol 3-kinase (PI 3-kinase) pathway of insulin signaling. Additionally, the study investigated whether a differential effect exists in male and female rodent offspring, such that females demonstrate decreased binding of p85 to IRS-1 after exposure to dexamethasone in utero.


METHODS
Timed-pregnant Sprague-Dawley rats received either tap water or dexamethasone in drinking water from day 13 of gestation until delivery. Fasting male and female offspring from each group were sacrificed on day 50 of life, and half of these rats were given insulin subcutaneously prior to sacrifice. Adipocyte, skeletal muscle, and liver cell lysates were analyzed by immunoprecipitation and Western blotting of IRS-1 and IRS-1-associated p85.


RESULTS
In all tissues examined, a significant inverse relationship was found between dexamethasone treatment in utero and association of p85 with IRS-1 in adulthood. p85 association with IRS-1 was similar in tissues from fasting and insulin-stimulated states. Furthermore, tissues of male and female rats demonstrated similar binding of p85 to IRS-1.


CONCLUSIONS
In a rat model, fetal exposure to dexamethasone was associated with decreased insulin signaling at the level of p85 binding to IRS-1, a proximal step in insulin signaling within the PI 3-kinase pathway. This effect did not appear to be enhanced by administration of insulin prior to sacrifice, nor was a sex-dependent differential effect noted.
O'Brien
Karen
K
Women and Infants' Hospital of Rhode Island, Providence, RI, USA. Karen_o'brien_MD@sshosp.org
Sekimoto
Hiroko
H
Boney
Charlotte
C
Malee
Maureen
M
D000818:Animals; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects*; D044882:Glucose Metabolism Disorders / Q000209:etiology; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005938:Glucocorticoids; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases