Novel hepatoselective insulin analog - Studies with a covalently linked thyroxyl-insulin complex in humans

OBJECTIVE - To test whether a thyroxyl-insulin analog with restricted acces s to receptor sites in peripheral tissues displays relative hepatoselectivi ty in humans. RESEARCH DESIGN AND METHODS - Five normal human subjects received a subcuta neous bolus injection of either N-alpha B1 L-thyroxyl-insulin (B1-T4-Ins) o r NPH insulin in random order. Insulin kinetics, relative effects on hepati c glucose production, and peripheral glucose uptake were studied using eugl ycemic clamp and stable isotope [D-6,6-H-2(2)]glucose) dilution techniques. Blood samples were taken for the determination of total immunoreactive ins ulin/analog concentrations and for liquid chromatography to assess the prot ein binding of the analog in the circulation. RESULTS - After subcutaneous administration, B1-T4-Ins was well tolerated a nd rapidly absorbed. The analog had a long serum half-life and was highly p rotein bound (similar to 86%). Its duration of action, as judged by the dur ation of infusion of exogenous glucose to maintain euglycemia, was similar to that of NPH insulin. The effect of the analogs on hepatic glucose produc tion was similar to that of NPH insulin, indicating equivalent hepatic pote ncy. The analog demonstrated less effect on peripheral glucose uptake than NPH insulin (P = 0.025), had no effect on metabolic clearance rate of gluco se, and exhibited a reduced capacity to inhibit lipolysis (P < 0.05). CONCLUSIONS - When injected subcutaneously into normal human subjects, B1-T 4-Ins is well tolerated, quickly absorbed, and highly protein bound, result ing in a long plasma half-life. This analog appears to have a hepatoselecti ve action, and, therefore, has the potential to provide more physiological insulin action than the insulin preparations currently used.