subcutaneous point of injection is retarded; these suspensions are achieved by creating
poorly water-soluble complexes of the anionic insulin with either polycationic protamine
in phosphate buffer (NPH insulin) or zinc in acetate buffer (lente, ultralente insulin). In
addition to these “formulation tricks,” a clever manipulation of peptide chemistry is used
to influence the pharmacokinetics of ultra-short-acting insulin. Ultra-short-acting insulin is
produced by recombinant DNA technology whereby two amino acids near the C-terminal
of the B-chain are reversed: the lysine at position B29 is moved to B28, and the proline
at B28 is moved to B29 (hence the name lispro insulin). This amino acid reversal does not
influence the ability of the resulting insulin analog to bind to insulin receptors, but it does
decrease the likelihood of the insulin molecule polymerizing to hexamers (common in
human insulin); accordingly, the lispro insulin remains in a monomeric form, enabling it
to be rapidly absorbed and to bind to receptors more quickly. These multiple preparations
of insulin enable “fine tuning” such that insulin receptors can be stimulated over a thera-
peutically desirable time frame. Indeed, standard insulin therapy frequently consists of
split-dose injections of mixtures of short-acting and intermediate-acting insulins.
The standard mode of insulin therapy has traditionally been by subcutaneous injec-
tion using disposable needles/syringes. However, other routes of administration, includ-
ing continuous subcutaneous insulin infusion pumps and inhalation of finely powdered
aerosolized insulin, are currently being explored.
Hypoglycemic Agents. Hypoglycemic agents are orally administered drugs (small
organic molecules) that lower the blood glucose level and substitute for the action of
insulin that is missing for any reason (insufficient insulin production, increased destruc-
tion, or the presence of anti-insulin antibodies). Oral antidiabetic agents can be divided
into four groups:
- Insulin secretagogs (e.g., sulfonylureas [1st and 2nd generations], meglitinides)
- Biguanides (e.g., metformin, phenformin)
- Thiazolidinediones (e.g., rosiglitazone, pioglitazone)
- α-Glucosidase inhibitors (e.g., acarbose, miglitol)
The insulin secretagogs increase insulin release from the pancreas. Within the pancreas,
sulfonylureas bind to a high-affinity sulfonylurea receptor that is associated with an
ATP-sensitive potassium ion channel. When a sulfonylurea binds to its receptor, the
efflux of potassium ions through the channel is inhibited; this causes cellular membrane
depolarization, which leads to opening of voltage-gated calcium channels, resulting in
calcium influx, which in turn produces a release of preformed insulin. The first gener-
ation sulfonylureas include tolbutamide (5.114), tolazamide (5.115), acetohexamide
(5.116), and chlorpropamide (3.24); all of these have somewhat short half-lives, apart
from chlorpropamide which has a half-life of 32 hours. The second generation sul-
fonylureas consist of glyburide (5.117), glipizide (5.118) and glimepiride (5.119). It is
debatable whether these agents have more efficacy than chlorpropamide, but they do
produce fewer side effects; there are some patients who fail on tolbutamide or tolaza-
mide, but who respond to a more potent second-generation agent. Meglitinides, such as
repaglinide (5.120), are a newer class of insulin secretagog. The insulin secretagogs are
widely used in the treatment of adult Type II diabetes.
HORMONES AND THEIR RECEPTORS 367