Diabetes in subjects with hepatocyte nuclear factor (HNF)-1α gene mutations (maturity-onset diabetes of the young [MODY]-3) is characterized by impaired insulin secretion. Surprisingly, MODY3 patients exhibit hypersensitivity to the hypoglycemic actions of sulfonylurea therapy. To study the pharmacogenetic mechanism(s), we have investigated glibenclamide-induced insulin secretion, glibenclamide clearance from the blood, and glibenclamide metabolism in wild-type and Hnf-1α-deficient mice. We show that despite a profound defect in glucose-stimulated insulin secretion, diabetic Hnf-1α-/- mice have a robust glibenclamide-induced insulin secretory response. We demonstrate that the half-life (t1/2) of glibenclamide in the blood is increased in Hnf-1α-/- mice compared with wild-type littermates (3.9 ± 1.3 vs. 1.5 ± 1.8 min, P ≤ 0.05). The clearance of glibenclamide from the blood during the first hours after intravenous administration was reduced approximately fourfold in Hnf-1α-/- mice compared with Hnf-1α+/+ littermates. Glibenclamide uptake into hepatocytes was dramatically decreased in vivo and in vitro. To study the metabolism of glibenclamide in Hnf-1α-/- animals, we analyzed liver extracts from [3H]glibenclamide-injected animals by reverse-phase chromatography. We found that the ratio of the concentrations of glibenclamide and its metabolites was moderately increased in livers of Hnf-1α-/- mice, suggesting that hepatic glibenclamide metabolism was not impaired in animals with Hnf-1α deficiency. Our data demonstrate that high serum glibenclamide concentrations and an increased t1/2 of glibenclamide in the blood of Hnf-1α-/- mice are caused by a defect in hepatic uptake of glibenclamide. This suggests that hypersensitivity to sulfonylureas in MODY3 patients may be due to impaired hepatic clearance and elevated plasma concentrations of the drug.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism