β-Cell Insulin Secretory Response to Oral Hypoglycemic Agents Is Blunted during Moderate Hypoglycemia
Abstract Number: 495-P
Authors: WALEED ALDHAHI, JENIFER ARMSTRONG, RICHARD D. CARR, CLARA BOUCHE, ALAN MOSES, ALLISON B. GOLDFINE
Institutions: Boston, MA; Bagsvaerd, Denmark
Results: Oral hypoglycemic agents that bind to the ATP-sensitive potassium channel lower glucose levels effectively in individuals with diabetes. While the principle mechanism of action also promotes hypoglycemia, profound hypoglycemia is rare. Decreased stimulation of insulin secretion by these agents at mild hypoglycemia could provide protection from more profound hypoglycemia. Sulfonylureas and meglitinides bind to both shared and unique sites on the ATP-sensitive potassium receptor/channel complex but have different pharmacokinetic profiles. To evaluate the differential ability of both sulfonylureas and meglitinides to stimulate insulin release at modest hypoglycemia, we evaluated dextrose infusion rates necessary to maintain plasma glucose after oral administration of repaglinide (1 mg) or glipizide (5mg) at euglycemia and again at modest hypoglycemia (∼ 50 mg/dl). Healthy subjects with no family history of diabetes underwent four clamp studies, two performed while maintaining isoglycemia (glucose levels at the fasted value) and two while maintaining modest hypoglycemia of 50 mg/dl induced by low dose insulin infusion (0.6 mU/kg/min). There was a marked decrease in the dextrose infusion rate with administration of either repaglinide or glipizide at hypoglycemia compared to drug administration at euglycemia (p≤0.006). This was accompanied by a reduction in C-peptide secretion (p≤0.001). While each drug demonstrated a unique PK profile, drug absorption was comparable at euglycemia or hypoglycemia. The mechanism accounting for the reduced dextrose requirement during hypoglycemia likely involves a markedly decreased insulin secretory response to the agents during hypoglycemia and suggests that at modest hypoglycemia, low glucose or other metabolite(s), or altered counter-regulatory hormone levels are sufficient to inhibit insulin release in response to potent insulin secretagogues. These findings may help to explain the relatively low incidence of severe hypoglycemia with clinical administration of these drugs.