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Am J Physiol Endocrinol Metab 293: E1451-E1458, 2007. First published September 25, 2007; doi:10.1152/ajpendo.00356.2007
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Increased hypothalamic-pituitary-adrenal axis activity and hepatic insulin resistance in low-birth-weight rats

Esben S. Buhl,1,2,3 Susanne Neschen,3 Shin Yonemitsu,3 Joerg Rossbacher,3 Dongyan Zhang,3 Katsutaro Morino,3 Allan Flyvbjerg,2 Pascale Perret,3 Varman Samuel,3 Jung Kim,4 Gary W. Cline,3 and Kitt Falk Petersen1,3

1Department of Pharmacology, Faculty of Health Sciences, Medical Department M, University of Aarhus; 2Medical Research Laboratory, Aarhus University Hospital, Aarhus Sygehus, Aarhus, Denmark; and Departments of 3Internal Medicine and 4Pathology, Yale University School of Medicine, New Haven, Connecticut

Submitted 9 June 2007 ; accepted in final form 12 September 2007

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 ~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.

gluconeogenesis; adrenocorticotropic hormone; corticosterone; type 2 diabetes


Address for reprint requests and other correspondence: K. F. Petersen, Yale University School of Medicine, Dept. of Internal Medicine, Section of Endocrinology, Cedar St. 333, P. O. Box 208020, New Haven, CT 06520-8020 (e-mail: kitt.petersen{at}yale.edu)






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