Design of Insulin Variants for Improved Treatment of Diabetes - Peptide and Protein Design for Biopharmaceutical Applications - page 248

person. Basal insulin levels should be present in the body 24 hours a day, and
extra supplies of insulin must be given for handling of the glucose ingested
with each meal. However, constant achievement of normal glucose levels is
near impossible for diabetes patients due to the many factors involved in
blood glucose fluctuations, such as meals of diverse character, exercise,
sleep, infections and endogenous glucose production by the liver [5].
Furthermore, intensive insulin treatment includes the risk of having the
blood sugar dropping too low, which is acutely dangerous. The ideal
therapeutic window for insulin dose is very narrow. Blood glucose levels
should ideally stay within the range 4-6 millimols per litre.

100

80

60

40

20

0

0800 1200 1600

Clock Time (hours)

2000 2400 0400

Figure 7.1 Average daily insulin secretion profile in healthy individuals. Insulin drug
delivery targets this pattern in pursuit of optimal glucose control, which lowers the
risk of long-term complications from diabetes. A selection of fast- and long-acting
insulins is required in order to approach this goal. Reproduced by permission of the
American Society for Clinical Investigation. Copyright 1988

In order to help the timing and dosing of the insulin drug, scientists
have engineered insulin toward achieving slower, faster and more pre-
dictable profiles than observed when using native insulin as drug.
The current chapter will review and evaluate the known approaches
for modulating insulin drug properties, with focus on structural engineer-
ing of the insulin molecule targeted toward modulation of insulin phar-
macology. Native insulin structure-activity relationships, insulin
chemistry and insulin biology have been the subjects of recent reviews
[6-8], and these topics will be included here only as necessary for follow-
ing the drug engineering discussion.
Searching for insulin in the public database Medline/PubMed in
January 2008 resulted in identification of 229 051 scientific papers.
Insulin is clearly one of the best-studied peptide hormones and drugs,