Increased hypothalamic-pituitary-adrenal axis activity and hepatic insulin resistance in low-birth-weight rats.
Individuals born with a low birth weight (LBW) have an increased prevalence of type 2 diabetes, but the mechanisms responsible for this association are unknown. Given the important role of insulin resistance in the pathogenesis of type 2 diabetes, we examined insulin sensitivity in a rat model of LBW due to intrauterine fetal stress. During the last 7 days of gestation, rat dams were treated with dexamethasone and insulin sensitivity was assessed in the LBW offspring by a hyperinsulinemic euglycemic clamp. The LBW group had liver-specific insulin resistance associated with increased levels of PEPCK expression. These changes were associated with pituitary hyperplasia of the ACTH-secreting cells, increased morning plasma ACTH concentrations, elevated corticosterone secretion during restraint stress, and an approximately 70% increase in 24-h urine corticosterone excretion. These data support the hypothesis that prenatal stress can result in chronic hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in increased plasma corticosterone concentrations, upregulation of hepatic gluconeogenesis, and hepatic insulin resistance.
Buhl
Esben S
ES
Department of Pharmacology, Faculty of Health Sciences, Medical Department M, University of Aarhus, Aarhus, Denmark.
Neschen
Susanne
S
Yonemitsu
Shin
S
Rossbacher
Joerg
J
Zhang
Dongyan
D
Morino
Katsutaro
K
Flyvbjerg
Allan
A
Perret
Pascale
P
Samuel
Varman
V
Kim
Jung
J
Cline
Gary W
GW
Petersen
Kitt Falk
KF
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D002784:Cholesterol / Q000097:blood; D003345:Corticosterone / Q000097:blood / Q000652:urine; D005215:Fasting / Q000097:blood; D005260:Female; D005947:Glucose / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D012149:Restraint, Physical / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood
D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D007334:Insulin-Like Growth Factor I; D000324:Adrenocorticotropic Hormone; D002784:Cholesterol; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose; D003345:Corticosterone