title: Effect of thyroid hormone binding proteins on insulin receptor binding of B1-thyronine-insulin analogues.
abstract: Certain thyronine-insulin analogues, which form non-covalent complexes with plasma proteins, have been shown to act preferentially in the liver. We hypothesized that this property may be dependent on the ability of the analogue to bind to the insulin receptor without prior dissociation from the binding protein. NaB1-L-thyroxyl-insulin, NaB1-3,3',5'-triiodothyronine-insulin, NaB1-D-thyroxyl-insulin and NaB1-L-thyroxyl-aminolauroyl-insulin were compared with insulin for their capacity to inhibit the binding of [125I]TyrA14-insulin to rat liver plasma membrane in albumin-free buffer. Effective doses at 50% maximum inhibition of binding (ED50) were calculated with and without addition of the thyroid hormone binding proteins transthyretin, thyroxine binding globulin and human serum albumin. The binding of thyronine-insulin analogues to insulin receptors was inhibited in a dose-dependent manner by the addition of thyroid hormone binding proteins at concentrations in the physiological range. Complexes of thyronine-insulin analogues with thyroid hormone binding proteins exhibit impaired insulin receptor binding affinities compared with those of the analogues in their free form. Hepatoselectivity in vivo may not depend on binding of the intact complexes to hepatocytes. These results have implications for the physiological role of hormone binding proteins and the in vivo properties of other insulin analogues which bind to plasma proteins.
authors.affiliation: Department of Diabetes, Endocrinology and Internal Medicine, St. Thomas' Hospital, Guy's, King's and St Thomas' School of Medicine, King's College, London SE1 7EH, UK. fariba.shojaee-moradie@kcl.ac.uk
authors.forename: Fariba
authors.initials: F
authors.lastname: Shojaee-Moradie
authors.forename: Michelle P Y
authors.initials: MP
authors.lastname: Chan
authors.forename: Micayla A
authors.initials: MA
authors.lastname: Telfer
authors.forename: Dietrich
authors.initials: D
authors.lastname: Brandenburg
authors.forename: Erik
authors.initials: E
authors.lastname: Sundermann
authors.forename: Heike
authors.initials: H
authors.lastname: Eckey
authors.forename: Jens
authors.initials: J
authors.lastname: Kleinjung
authors.forename: Achim
authors.initials: A
authors.lastname: Schüttler
authors.forename: Richard H
authors.initials: RH
authors.lastname: Jones
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002850:Chromatography, Gel / Q000379:methods; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000737:chemistry / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011972:Receptor, Insulin / Q000737:chemistry / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D013975:Thyroxine-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D007328:Insulin; D008565:Membrane Proteins; D011972:Receptor, Insulin; D013963:Thyroid Hormones; D013975:Thyroxine-Binding Proteins; D000097810:Thyroid Hormone-Binding Proteins; C417090:thyroxyl-insulin