Effect of glyburide on in vivo recycling of the hepatic insulin receptor.
Sulfonylureas affect insulin action at both receptor and post-receptor sites, but their exact mechanism is poorly understood. In these studies, a novel technique was used to examine the influence of glyburide on in vivo cycling of the hepatic insulin receptor. Rats were gavage-fed with 5 mg/kg per day of glyburide solubilized in 60 percent polyethylene glycol and 40 percent phosphate buffer. Control rats were fed polyethylene glycol and buffer alone. After seven days, each rat was anesthetized, the abdomen was surgically exposed, and the animal was given a saturating bolus of 30 micrograms of unlabeled insulin via the portal vein. At seven specified times from 10 seconds to 45 minutes later, a second portal vein injection of a mixture of 1.5 microCi (0.015 micrograms) 125I-labeled insulin and 15 microCi 3HOH (a highly diffusible internal reference marker) was administered; 18 seconds later (time for one circulation), the right lobe of the liver was removed, and 125I and 3H values were counted. The liver uptake index and the turnover half-time were then calculated. Glyburide caused a doubling of the turnover half-time for the receptor. This suggests that sulfonylureas potentiate the action of insulin either by increasing the dwell time of insulin on its receptor or by affecting an intracellular event that delays the recycling of the insulin receptor back to the cell surface plasma membrane. The technique is potentially useful as an in vivo screening assay for the effects of other drugs and hormones on the liver.
D000818:Animals; D005110:Extracellular Space; D005905:Glyburide / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007457:Iodine Radioisotopes; D008099:Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin / Q000187:drug effects*
D007328:Insulin; D007457:Iodine Radioisotopes; D011972:Receptor, Insulin; D005905:Glyburide