Evaluation of the relationship between hyperinsulinaemia and myocardial ischaemia/reperfusion injury in a rat model of depression

Major depression is associated with medical comorbidity such as ischaemic heart disease and diabetes but the underlying pathophysiological mechanisms remain unclear. The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression exhibiting features similar to those of depressed individuals. The aim of the present study was to compare the myocardial responsiveness to ischaemia-reperfusion injury and effects of ischaemic preconditioning (IPC) in hearts from FSL rats using Sprague-Dawley (SD) rats as controls and to characterize differences in glucose metabolism and insulin sensitivity between the FSL and SD rats. Hearts were perfused in a Langendorff model and subjected or not to IPC before 40 minutes of global ischaemia followed by 120 minutes of reperfusion. Myocardial infarct size was found to be significantly larger in the FSL rats (I/R: 62.4±4.2 vs. 46.9±2.9%, P<0.05) than in the SD rats. IPC reduced the infarct size (P<0.01) and improved haemodynamic function (P<0.01) in both the FSL and the SD rats. No significant difference was found in blood glucose levels between the two groups measured after 12 hours of fasting but fasting plasma insulin (70.1±8.9 vs. 40.9±4.7 pmol/l, P<0.05) and HOMA (homeostatic model assessment) index (P<0.01) were significantly higher in the FSL rats compared to the SD rats. In conclusion, FSL rats had larger infarct sizes and were found to be hyperinsulinaemic compared to SD rats but seemed to have a maintained cardioprotective mechanism against ischaemia-reperfusion injury as IPC reduced infarct size in these rats. This animal model may be useful in future studies when examining the mechanisms that contribute to the cardiovascular complications associated with depression

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

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 Ser473 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 Ser473 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 Ser473 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