Design of Insulin Variants for Improved Treatment of Diabetes - Peptide and Protein Design for Biopharmaceutical Applications - page 249

and a review of all aspects of insulin literature is not intended here. Even
within the given scope, the cited papers are only a selection.
The text is intended for nonspecialists of insulin and diabetes, so terms
from the field of diabetology and other technical terms are explained as
they first appear.

7.2 DIABETES MANAGEMENT AND THE NEED FOR

INSULIN ENGINEERING

In a fasted, healthy person, blood glucose is tightly regulated near 5
millimols per litre (millimolar, mM). Human cells uptake and metabolize
glucose as part of the body's energy balance, and the cellular glucose
uptake is regulated by insulin via binding and activation of the insulin
receptor present on cellular surfaces. Basal levels of insulin are required 24
hours a day. The pancreatic b-cells continuously excrete insulin in the
needed amounts, and sensing mechanisms in the b-cells ensure that insulin
is excreted in levels necessary to maintain the glucose level in the normal
range of 4-6 mM [9]. Following a meal, blood glucose can rise to around
10 mM, but this rise is countered by excretion of extra insulin (bolus
insulin) from the b-cells in order to increase glucose uptake and bring
the glucose level back to normal. The insulin secretion is stimulated not
just by glucose, but also by incretine hormones like glucagon-like peptide 1
(GLP-1), which is secreted from gut L -cells in response to a meal [10].
Insulin is produced in the b-cells as inactive single-chain proinsulin
[11], which is subsequently processed to active two-chain insulin and
stored in the b-cells as zinc(II) insulin hexamer granules. In case of
exercise or fasting, where blood glucose levels may drop below normal,
the pancreatic a-cells will excrete glucagon [12], which in turn stimulates
the liver to produce glucose from stored glycogen, thereby maintaining
the normal glucose level.
There are two main types of diabetes, type 1 and type 2, both diagnosed
by raised blood glucose levels. Type 1 diabetes often appears at a young
age and is also known as juvenile-onset diabetes. Type 1 is an autoim-
mune disorder. The insulin-producing b-cells are killed by the immune
system, for reasons that are not fully understood. Genetic disposition is
well-documented and infection or shock may play a role [13]. The pro-
gression of type 1 diabetes is quite fast, and blood glucose levels at the
time of diagnosis are often very high, > 30 mM, which results in excessive
excretion of glucose in the urine, weight loss and craving thirst, and these