Treatment with an SSRI antidepressant restores hippocampo-hypothalamic corticosteroid feedback and reverses insulin resistance in low-birth-weight rats

Abstract

Low birth weight (LBW) is associated with type 2 diabetes and depression, which may be related to prenatal stress and insulin resistance as a result of chronic hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. We examined whether treatment with a selective serotonin reuptake inhibitor [escitalopram (ESC)] could downregulate HPA axis activity and restore insulin sensitivity in LBW rats. After 4-5 wk of treatment, ESC-exposed LBW (SSRI-LBW) and saline-treated control and LBW rats (Cx and LBW) underwent an oral glucose tolerance test or a hyperinsulinemic euglycemic clamp to assess whole body insulin sensitivity. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression and red skeletal muscle PKB Ser(473) phosphorylation were used to assess tissue-specific insulin sensitivity. mRNA expression of the hypothalamic mineralocorticoid receptor was fivefold upregulated in LBW (P < 0.05 vs. Cx), accompanied by increased corticosterone release during restraint stress and total 24-h urinary excretion (P < 0.05 vs. Cx), whole body insulin resistance (P < 0.001 vs. Cx), and impaired insulin suppression of hepatic PEPCK mRNA expression (P < 0.05 vs. Cx). Additionally, there was a tendency for reduced red muscle PKB Ser(473) phosphorylation. The ESC treatment normalized corticosterone secretion (P < 0.05 vs. LBW), whole body insulin sensitivity (P < 0.01) as well as postprandial suppression of hepatic mRNA PEPCK expression (P < 0.05), and red muscle PKB Ser(473) phosphorylation (P < 0.01 vs. LBW). We conclude that these data suggest that the insulin resistance and chronic HPA axis hyperactivity in LBW rats can be reversed by treatment with an ESC, which downregulates HPA axis activity, lowers glucocorticoid exposure, and restores insulin sensitivity in LBW rats.

Fig. 1.

Restraint stress test. Plasma corticosterone concentrations during restraint. Data are given as means ± SE. *P < 0.05 vs. selective serotonin reuptake inhibitor-low-birth-weight (SSRI-LBW) and saline-treated control (Cx) rats; †P < 0.01 vs. SSRI-LBW and Cx; ‡P < 0.01, LBW vs. SSRI-LBW and Cx.

Fig. 2.

A: oral glucose tolerance test (OGTT). Full blood glucose concentrations are shown before and after administration of 2.5 g glucose/kg body wt given by gavage. Data are given as means ± SE. *P < 0.01, SSRI-LBW vs. LBW; †P < 0.05, LBW vs. SSRI-LBW and Cx. B: hepatic phosphoenolpyruvate carboxykinase (PEPCK) mRNA expressions in the basal (i.e., fasted overnight for 12 h) and the postprandial state [i.e., tissues taken out 90 min after glucose gavage (OGTT)]. Data are given as means ± SE. *P < 0.05 vs. SSRI-LBW and Cx.

Fig. 3.

A: mean rates of glucose infusion from 90 to 150 min after initiation of the hyperinsulinemic euglycemic clamp experiment. Data are given as means ± SE. *P < 0.01 vs. SSRI-LBW and Cx. B: rates of insulin-stimulated glucose transport activities in red (RG) and white (WG) gastrocnemic muscle tissue as well as in epididymidal fat pads. Data are given as means ± SE. *P < 0.01 vs. Cx and P < 0.05, SSRI-LBW.