Monomeric insulins obtained by protein engineering and their medical implications.
The use of insulin as an injected therapeutic agent for the treatment of diabetes has been one of the outstanding successes of modern medicine. The therapy has, however, had its associated problems, not least because injection of insulin does not lead to normal diurnal concentrations of insulin in the blood. This is especially true at meal times when absorption from subcutaneous tissue is too slow to mimic the normal rapid increments of insulin in the blood. In the neutral solutions used for therapy, insulin is mostly assembled as zinc-containing hexamers and this self-association, which under normal physiological circumstances functions to facilitate proinsulin transport, conversion and intracellular storage, may limit the rate of absorption. We now report that it is possible, by single amino-acid substitutions, to make insulins which are essentially monomeric at pharmaceutical concentrations (0.6 mM) and which have largely preserved their biological activity. These monomeric insulins are absorbed two to three times faster after subcutaneous injection than the present rapid-acting insulins. They are therefore capable of giving diabetic patients a more physiological plasma insulin profile at the time of meal consumption.
Brange
J
J
Novo Research Institute, Bagsvaerd, Denmark.
Ribel
U
U
Hansen
J F
JF
Dodson
G
G
Hansen
M T
MT
Havelund
S
S
Melberg
S G
SG
Norris
F
F
Norris
K
K
Snel
L
L
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002942:Circular Dichroism; D003196:Computer Graphics; D005818:Genetic Engineering; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000235:genetics* / Q000494:pharmacology / Q000627:therapeutic use; D046911:Macromolecular Substances; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013552:Swine
D001786:Blood Glucose; D007328:Insulin; D046911:Macromolecular Substances