Submitted on June 9, 2007
Accepted on September 12, 2007
Increased Hypothalamic-Pituitary-Adrenal Axis Activity and
Hepatic Insulin Resistance in Low Birth Weight Rats
Esben S Buhl1, Susanne Neschen2, Shin Yonemitsu3, Joerg Rossbacher3, Dongyan Zhang3, Katsutaro Morino3, Allan Flyvbjerg4, Pascale Perret5, Varman Samuel, Jung Kim6, Gary W. Cline7, and Kitt Falk Petersen8*
1 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States; Medical Department M, Aarhus University Hospital, Aarhus, Denmark
2 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States; Internal Medicine, Yale university School of Medicine, Connecticut, United States
3 Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States
4 Medical Research Lab, Aarhus University Hospital, Aarhus, Denmark
5 Internal Medicine, Yale Unversity School of Medicine, New Haven, Connecticut, United States
6 Department of Physiology, Yale University School of Medicine, New Haven, Connecticut, United States
7 Dept. of Internal Med., Sect. of Endocrinology, Fitkin 1, Yale University School of Medicine, New Haven,, Connecticut, United States
8 Internal Medicine Endocrinology, Yale University School of Medicine, New Haven, Connecticut, United States
* To whom correspondence should be addressed. E-mail: kitt.petersen{at}yale.edu.
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, as well as an approximately 70% increase in 24 hour 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, up-regulation of hepatic gluconeogenesis and hepatic insulin resistance.
