Study Of Central Diuretic Effect Of Exenatide

Exenatide, a well-known synthetic polypeptide long-acting agonist ofglucogan-like peptide-1(GLP-1) receptor, is an effective drug to treat type2diabetes.This study aimed to investigate the central diuretic effect of exenatide.Methods: Exenatide was administered intrathecally and intracerebroventricularly,then urine was collected to reflect the strength of the diuretic effect. the urine volumewas gauged and the ion concentrations was detected. Two kinds of GLP-1receptoragonists was administered to compare with exenatide. GLP-1receptor antagonist andgene silencer siRNA/GLP-1receptor were applied to try to block the spinal diureticeffect of exenatide. GLP-1and DPP-4inhibitor were administered intrathecally. Twokinds of PKA inhibitors were applied to try to block the spinal diuretic effect ofexenatide. Levels of antidiuretic hormone and aldosterone in cerebrospinal fluid andserum were detected after intrathecal injection of exenatide.Results: Intrathecal and intracerebroventricular injections of exenatide causedintense diuretic effect in rats, which was comparable to that of furosemide. The urinewas neutral and hypisotonic after administration of exenatide. However, two chemicalmolecular agonists of GLP-1receptor had no diuretic effect. Meanwhile, exendin(9-39), the antagonist of GLP-1receptor could not block the spinal diuretic effect ofexenatide, and gene silencer siRNA/GLP-1receptor could not influence the spinaldiuretic effect of exenatide. Intrathecal injection of GLP-1caused diuretic effect. PKAinhibitors could not block the spinal diuretic effect of exenatide. Levels of antidiuretichormone and aldosterone in cerebrospinal fluid and serum increased maybe becauseof the loss of water and sodium caused by exenatide.The results showed that intrathecal injection of exenatide can cause intensediuretic effect and the mechanism is not clear yet, but it may not be mediated by theactivation of the well-known typical GLP-1receptor, i.e. there may be another type ofGLP-1receptor existing in the spinal cord.