Glucagon-like peptide-1 (GLP-1) is the main incretin that ensures insulin secretion and normalization of postprandial glycemia. GLP-1 mimetics are used for treatment of type 2 diabetes mellitus and obesity. Besides the insulinotropic effect, GLP-1 and its mimetics have been shown to affect on the functions of the cardiovascular and endocrine systems, the central mechanisms of appetite and metabolism regulation, the ion-regulatory and osmoregulatory renal functions, and a paradoxical hyperglycemic effect of incretin mimetics was also discovered. In current work the mechanisms by which the sympathoadrenal system is involved in the development of hyperglycemic and natriuretic effects of the GLP-1 mimetic exenatide in rats were studied. Experiments with healthy rats revealed that GLP-1 and its mimetic exenatide augmented the renal sodium excretion. Exenatide at doses of 0.15-5 nmol/kg, but not GLP-1 (1.5 nmol/kg), showed a hyperglycemic effect (blood glucose increased to 7.2–9.1 mM during the first hour). It has been shown that the rise of blood glucose level in rats administrated with incretin mimetic was associated with increase in renal excretion of catecholamine metabolites, was delayed by preliminary injection of a ganglionic blocker (pentamine 30 mg/kg) and was considerably leveled by non-selective β- and selective β2-adrenergic blockers (propranolol 5 mg/kg, ICI-118551 1 mg/kg). A significant modulation of natriuresis was revealed in response to the administration of exenatide during blockade of various adrenergic receptors subtypes. α1- and α2-blockers appreciably reduced (by 80%), and β1- and β2-blockers increased (by 150%) exenatide-stimulated renal sodium excretion. Thus, the data obtained indicate on the exenatide-induced activation of the sympathoadrenal system, which modulates the direction and severity of the incretin mimetic effects on blood glucose level and renal sodium excretion in healthy animals. The potential action on the sympathoadrenal system is important to consider when assessing the risk of adverse side effects during incretin mimetic therapy.
Read full abstract