Evidence is available that exendin-4 (EX4), a glucagon-like peptide-1 receptor (GLP-1R) agonist acutely stimulates hypothalamo-pituitary-adrenal (HPA) axis in the rat. EX4 is a potent insulinotropic agent, which is currently under clinical trial for treatment of type 2 diabetes. Since diabetes is known to affect adrenal function, we investigated the effects of the prolonged administration of EX4 and/or the GLP-1R antagonist EX4(9-39) (EX4-A) (daily subcutaneous injections of 1 nmol/kg EX4 and/or EX4-A, for 7 days) on the HPA axis of normoglycemic and streptozotocin (STZ)-induced diabetic rats. In STZ-untreated rats, chronic EX4 treatment did not change the blood level of ACTH. In contrast, it evoked a marked rise in the plasma concentrations of aldosterone and corticosterone, these effects being reversed by EX4-A. In STZ-induced diabetic rats, prolonged EX4 administration increased the plasma levels of ACTH, aldosterone and corticosterone. EX4-A did not prevent the first two effects of EX4, and annulled the latter one. These findings allow us to draw the following conclusions: i) EX4 prolonged exposure desensitizes hypothalamo-hypophyseal GLP-1R in normal rats, and exerts an ACTH-independent GLP-1R-mediated aldosterone and corticosterone secretagogue effect; and ii) experimental diabetes induces the expression of EX4 receptors other than the classic GLP-1R, whose activation mediate the ACTH and aldosterone, but not corticosterone, secretagogue effects. Our study provides evidence that metabolic dysregulations occurring in STZ-induced diabetic rats are able to profoundly affect the response of the HPA axis to GLP-1.

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