Linked Life Data

12475773

Source:http://linkedlifedata.com/resource/pubmed/id/12475773

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pubmed-article:12475773pubmed:abstractTextDiabetes in subjects with hepatocyte nuclear factor (HNF)-1alpha 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-1alpha-deficient mice. We show that despite a profound defect in glucose-stimulated insulin secretion, diabetic Hnf-1alpha(-/-) 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-1alpha(-/-) mice compared with wild-type littermates (3.9 +/- 1.3 vs. 1.5 +/- 1.8 min, P <or= 0.05). The clearance of glibenclamide from the blood during the first hours after intravenous administration was reduced approximately fourfold in Hnf-1alpha(-/-) mice compared with Hnf-1alpha(+/+) littermates. Glibenclamide uptake into hepatocytes was dramatically decreased in vivo and in vitro. To study the metabolism of glibenclamide in Hnf-1alpha(-/-) animals, we analyzed liver extracts from [(3)H]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-1alpha(-/-) mice, suggesting that hepatic glibenclamide metabolism was not impaired in animals with Hnf-1alpha deficiency. Our data demonstrate that high serum glibenclamide concentrations and an increased t(1/2) of glibenclamide in the blood of Hnf-1alpha(-/-) 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.lld:pubmed
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pubmed-article:12475773pubmed:volume51 Suppl 3lld:pubmed
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pubmed-article:12475773pubmed:dateRevised2011-11-17lld:pubmed
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pubmed-article:12475773pubmed:articleTitleDecreased glibenclamide uptake in hepatocytes of hepatocyte nuclear factor-1alpha-deficient mice: a mechanism for hypersensitivity to sulfonylurea therapy in patients with maturity-onset diabetes of the young, type 3 (MODY3).lld:pubmed
pubmed-article:12475773pubmed:affiliationLaboratory of Metabolic Diseases, the Rockefeller University, New York, New York 10021, USA.lld:pubmed
pubmed-article:12475773pubmed:publicationTypeJournal Articlelld:pubmed
pubmed-article:12475773pubmed:publicationTypeResearch Support, U.S. Gov't, P.H.S.lld:pubmed
pubmed-article:12475773pubmed:publicationTypeResearch Support, Non-U.S. Gov'tlld:pubmed
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