Novel hepatoselective insulin analog: studies with a covalently linked thyroxyl-insulin complex in humans.
OBJECTIVE
To test whether a thyroxyl-insulin analog with restricted access to receptor sites in peripheral tissues displays relative hepatoselectivity in humans.


METHODS
Five normal human subjects received a subcutaneous bolus injection of either N(alphaBl) L-thyroxyl-insulin (Bl-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)H2]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, Bl-T4-Ins was well tolerated and rapidly absorbed. The analog had a long serum half-life and was highly protein bound (approximately 86%). 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 < 0.05).


CONCLUSIONS
When injected subcutaneously into normal human subjects, Bl-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.
Shojaee-Moradie
F
F
Department of Diabetes, Endocrinology and Internal Medicine, Guy's King's and St. Thomas' School of Medicine, King's College London, St. Thomas' Hospital, UK.
Powrie
J K
JK
Sundermann
E
E
Spring
M W
MW
Schüttler
A
A
Sönksen
P H
PH
Brandenburg
D
D
Jones
R H
RH
D000328:Adult; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003903:Deuterium; D015309:Glucose Clamp Technique; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D007336:Insulin, Isophane / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011865:Radioisotope Dilution Technique
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C417090:thyroxyl-insulin; D007336:Insulin, Isophane; D003903:Deuterium