Decreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1α-deficient mice: A mechanism for hypersensitivity to sulfonylurea therapy in patients with maturity-onset diabetes of the young, type 3 (MODY3)

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 (t_1/2) 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 t_1/2 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.