Abbreviations: AUC, area under the curve; AUCR a , area under the curve calculated for glucose R a ; AUCR d , area under the curve calculated for glucose R d ; B1-T4-Ins, N ␣B L-thyroxyl-insulin; CV, coefficient of variation; FPLC, fast protein liquid chromatography; GINF, exogenous glucose infusion; IRI, immunoreactive insulin; MCR, metabolic clearance rate; NEFA, nonesterified free fatty acid; R a , glucose production; R d , glucose disposal; RIA, radioimmunoassay; TBG, thyroxine binding protein; THBP, thyroid hormone binding protein; TSH, thyroid-stimulating hormone.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. Novel Hepatoselective Insulin AnalogStudies with a covalently linked thyroxyl-insulin complex in humansOBJECTIVE -To test whether a thyroxyl-insulin analog with restricted access to receptor sites in peripheral tissues displays relative hepatoselectivity in humans.RESEARCH DESIGN AND METHODS -Five normal human subjects received a subcutaneous bolus injection of either N ␣B1 L-thyroxyl-insulin (B1-T4-Ins) or NPH insulin in random order. Insulin kinetics, relative effects on hepatic glucose production, and peripheral glucose uptake were studied using euglycemic clamp and stable isotope [D-6,6-2 H 2 ]glucose) dilution techniques. Blood samples were taken for the determination of total immunoreactive insulin/analog concentrations and for liquid chromatography to assess the protein binding of the analog in the circulation.RESULTS -After subcutaneous administration, B1-T4-Ins was well tolerated and rapidly absorbed. The analog had a long serum half-life and was highly protein bound (ϳ86%). Its duration of action, as judged by the duration of infusion of exogenous glucose to maintain euglycemia, was similar to that of NPH insulin. The effect of the analogs on hepatic glucose production was similar to that of NPH insulin, indicating equivalent hepatic potency. The analog demonstrated less effect on peripheral glucose uptake than NPH insulin (P = 0.025), had no effect on metabolic clearance rate of glucose, and exhibited a reduced capacity to inhibit lipolysis (P Ͻ 0.05).CONCLUSIONS -When injected subcutaneously into normal human subjects, B1-T4-Ins is well tolerated, quickly absorbed, and highly protein bound, resulting in a long plasma halflife. This analog appears to have a hepatoselective action, and, therefore, has the potential to provide more physiological insulin action than the insulin preparations currently used. E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s
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.
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