Effect of thyroid hormone binding proteins on insulin receptor binding of B1-thyronine-insulin analogues

TY - JOUR

T1 - Effect of thyroid hormone binding proteins on insulin receptor binding of B1-thyronine-insulin analogues

AU - Shojaee-Moradie, F

AU - Chan, M P Y

AU - Telfer, M A

AU - Brandenburg, D

AU - Sundermann, E

AU - Eckey, H

AU - Kleinjung, J

AU - Schuttler, A

AU - Jones, R H

PY - 2004/7/1

Y1 - 2004/7/1

N2 - 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 dependant on the ability of the analogue to bind to the insulin receptor without prior dissociation from the binding protein. N-alphaB1-L-thyroxyl-insulin, N-alphaB1-3,3',5-triiodothyronine-insulin, N-alphaB1-D-thyroxyl-insulin and N-alphaB1-L-thyroxyl-aminolauroyl-insulin were compared with insulin for their capacity to inhibit the binding of [I-125]Tyr(A14)-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-dependant 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. Hepato-selectivity 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.

AB - 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 dependant on the ability of the analogue to bind to the insulin receptor without prior dissociation from the binding protein. N-alphaB1-L-thyroxyl-insulin, N-alphaB1-3,3',5-triiodothyronine-insulin, N-alphaB1-D-thyroxyl-insulin and N-alphaB1-L-thyroxyl-aminolauroyl-insulin were compared with insulin for their capacity to inhibit the binding of [I-125]Tyr(A14)-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-dependant 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. Hepato-selectivity 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.

UR - http://www.scopus.com/inward/record.url?scp=3142667510&partnerID=8YFLogxK

M3 - Article

VL - 381

SP - 51

EP - 57

JO - Biochemical Journal

JF - Biochemical Journal

IS - 1

ER -