Increased hypothalamic-pituitary-adrenal axis activity and hepatic insulin resistance in low-birth-weight rats

Abstract

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.

Fig. 1

Insulin-stimulated glucose metabolism in 40-day-old control and low-birth-weight (LBW) rats. A: plasma glucose concentrations during the euglycemic hyperinsulinemic clamp. ○Controls; ●LBW. B: plasma [3-³H]glucose-specific activity during the euglycemic hyperinsulinemic clamp. ○Controls; ●LBW. C: rates of insulin-stimulated glucose infusion (GIR; n = 10–12). D: rates of glucose disappearance (Rd; n = 10–12).

Fig. 2

Hepatic glucose metabolism. A: rates of fasting and insulin-stimulated hepatic glucose production (HGP) in control and LBW rats (n = 10–12). B: %Insulin suppression of HGP (n = 10–12). C: fasting and insulin-stimulated hepatic phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression in control and LBW rats (n = 5–10).

Fig. 3

Corticosterone secretion in control and LBW rats. A: 24-h urinary corticosterone excretion in control and LBW rats (n = 8–12). B: plasma corticosterone increase above basal during restraint stress tests (n = 6). *P < 0.04, control vs. LBW.

Fig. 4

Morphology and number of pituitary ACTH-secreting cells and fasting at 8 AM. Plasma ACTH concentrations in control and LBW rats. A: immunohistochemical staining for ACTH in the lateral lobe of the pituitary in a control rat (magnification: 1:100, 57 ACTH-positive cells in shown section). B: immunohistochemical staining for ACTH in the pituitary lateral lobe of a LBW rat (magnification: 1:100, 64 ACTH-positive cells in shown section). C: quantification of ACTH-positive cells in a random area of the lateral lobe of the pituitary in LBW rats. Number of ACTH positive cells expressed as %number of ACTH positive cells in control lateral pituitary lobe (n = 9–10). D: plasma ACTH concentrations at 8 AM, after 14 h of fasting, in control and LBW rats (n = 9–10).