TY - JOUR
T1 - Decreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1α-deficient mice
T2 - A mechanism for hypersensitivity to sulfonylurea therapy in patients with maturity-onset diabetes of the young, type 3 (MODY3)
AU - Boileau, Pascal
AU - Wolfrum, Christian
AU - Shih, David Q.
AU - Yang, Tien An
AU - Wolkoff, Allan W.
AU - Stoffell, Markus
PY - 2002/12/1
Y1 - 2002/12/1
N2 - 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.
AB - 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.
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U2 - 10.2337/diabetes.51.2007.s343
DO - 10.2337/diabetes.51.2007.s343
M3 - Article
C2 - 12475773
AN - SCOPUS:0036895595
SN - 0012-1797
VL - 51
SP - S343-S348
JO - Diabetes
JF - Diabetes
IS - SUPPL. 3
ER -