Beta-cell insulin secretory response to oral hypoglycemic agents is blunted in humans in vivo during moderate hypoglycemia.

Waleed Aldhahi, Jen Armstrong, Clara Bouche, Richard D Carr, Alan Moses, Allison B Goldfine

Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA.

The Journal of clinical endocrinology and metabolism 2004 Sep

filter terms:

Oral hypoglycemic agents bind to the ATP-sensitive potassium channel and lower glucose levels effectively in individuals with diabetes. Although the principle mechanism of action can also promote hypoglycemia, clinically 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 (5 mg) at euglycemia and again at modest hypoglycemia. 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 2.78 mmol/liter (50 mg/dl) induced by low-dose insulin infusion (3.6 pmol/kg.min). There was a marked decrease in the dextrose infusion rate with administration of either repaglinide or glipizide at hypoglycemia compared with drug administration at euglycemia (P C peptide secretion (P pharmacokinetic profile, drug absorption was comparable at euglycemia and 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 counterregulatory 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.

Citation

Waleed Aldhahi, Jen Armstrong, Clara Bouche, Richard D Carr, Alan Moses, Allison B Goldfine. Beta-cell insulin secretory response to oral hypoglycemic agents is blunted in humans in vivo during moderate hypoglycemia. The Journal of clinical endocrinology and metabolism. 2004 Sep;89(9):4553-7