C h a p t e r 3 3
Diabetes Mellitus and the Metabolic Syndrome
809
sucrose (table sugar), whose breakdown may be blocked
by the action of the
α
-glucosidase inhibitors.
Thiazolidinediones.
The thiazolidinediones (TZDs)
or glitazones (e.g., pioglitazone, rosiglitazone) are the
only class of drugs that directly target insulin resis-
tance. They do this by increasing insulin sensitivity in
the insulin-responsive tissues—liver, skeletal muscle,
and fat—allowing the tissues to respond to endoge-
nous insulin more efficiently without increased output
from already dysfunctional beta cells.
3,32
Because of
the previous problem with liver toxicity in this class of
drugs, liver enzymes should be monitored before start-
ing therapy according to guidelines. Both agents can
cause fluid accumulation and are therefore contraindi-
cated in patients with stage III and IV heart failure
33
(see Chapter 20, Table 20-1). Other potential adverse
effects include an increased risk of bone fractures
34
and
of bladder cancer.
Incretin-BasedAgents.
Incretins are hormones released
into the circulation by the gastrointestinal tract after a
meal, especially one high in carbohydrates, that amplify
the glucose-induced release of insulin (see Chapter
28).
3,6
The main incretins secreted are glucagon-like
peptide 1 (GLP-1) and glucose-dependent insulinotropic
polypeptide (GIP).
3,35,36
Both GLP-1 and GIP are rapidly
degraded by the enzyme dipeptidyl peptidase-4 (DPP-4).
DPP-4 enzyme inhibitors work by inhibiting the DPP-4
enzyme and increasing GLP-1 and GIP levels, which
then increase insulin release. Glucagon-like peptide 1
also helps to suppress glucagon release.
Exenatide, a synthetic analog of GLP-1 that is resis-
tant to DPP-4 degradation, is approved as an injectable
adjunctive therapy for people with type 2 diabetes. The
drug has been shown to have multiple actions such as
potentiation of glucose-mediated insulin release, slowed
gastric emptying, and a central loss of appetite. Although
exenatide was the first GLP-1 agonist to be developed
and approved, other agents and formulations have also
been approved.
36
Many other novel classes of antidiabetes agents are
also approved for type 2 diabetes including the SGLT2
inhibitor, canagliflozin. This agent, which works by
inhibiting glucose reabsorption from the kidney, results
in about 70 g (approximately 300 Kcal) glucose loss per
day. The adverse effects are understandable, including
polyuria due to osmotic diuresis and increased urinary
tract infections and genitourinary
Candida
infections.
Insulin
Type 1 diabetes mellitus always requires treatment with
insulin, and many people with type 2 diabetes eventually
require insulin therapy. Insulin is destroyed in the gas-
trointestinal tract and must be administered by injection
or inhalation. An inhaled form of insulin (Exubera) was
on the market for a short time in the United States but
was withdrawn for commercial reasons. Other inhaled
insulin formulations are in clinical development.
Human insulin has become widely available, pro-
viding an alternative to forms of insulin obtained from
bovine and porcine sources. Its manufacture uses recom-
binant deoxyribonucleic acid (DNA) technology. More
recently, analogs to human insulin have become avail-
able that offer even better and more reproducible release
characteristics.
37
Four insulin types are classified by length and peaking
of action: short acting, rapid acting, intermediate act-
ing, and long acting.
32,37
Short-acting insulin
(regular) is
a soluble crystalline insulin whose effects begin within
30 minutes after subcutaneous injection and generally
last for 5 to 8 hours. The
rapid-acting insulins
(lispro,
aspart, glulisine) are produced by recombinant technol-
ogy and have a more rapid onset, peak, and duration of
action than short-acting regular insulin. The rapid-acting
K channel
+
K
+
Sulfonylureas
Glucose
transporter
Glucose
ATP
Metabolism
Insulin
granules
Ca
++
channel
depolarizing
opens
Insulin
Ca
++
FIGURE 33-9.
One model of control of
release of insulin by the pancreatic beta
cells and the action of the sulfonylurea
agents. In the resting beta cell with low
adenosine triphosphate (ATP) levels,
potassium diffuses through the ATP-
gated channels, maintaining the resting
membrane potential. As blood glucose
rises and is transported into the beta
cell by the glucose transporter, ATP
rises, causing the potassium channels
to close and depolarization to occur.
Depolarization results in opening of the
voltage-gated calcium channels, which
leads to insulin secretion. (Modified from
Karam JH.Type II diabetes and syndrome
X. Endocrinol Metab Clin North Am.
1992;21(2):329–350.)
