814
U N I T 9
Endocrine System
hyperglycemia is the best-established concomitant factor
associated with diabetic complications.
48,49
The Diabetes
Control and Complications Trial (DCCT) and its ongo-
ing long-term observational study, the Epidemiology of
Diabetes Interventions and Complications Study (EDIC)
conducted in 1441 patients with type 1 diabetes, demon-
strated that the incidence of retinopathy, nephropathy,
and neuropathy can be reduced by intensive glycemic
control.
49
Similar results have been demonstrated by the
United Kingdom Prospective Diabetes Study (UKPDS) in
5000 patients with type 2 diabetes.
50
Theories of Pathogenesis
The interest among researchers in explaining the causes
and development of chronic lesions in a person with
diabetes has led to a number of theories. At least three
distinct metabolic pathways have been proposed in long-
term complications of diabetes: intracellular hypergly-
cemia and disturbance in polyol pathways, formation
of advanced glycation end products, and activation of
protein kinase C.
3,48,51
Polyol Pathway.
A polyol is an organic compound
that contains three or more hydroxyl (OH) groups.
The polyol pathway refers to the intracellular mecha-
nisms responsible for changing the number of hydroxyl
units on a glucose molecule. In the sorbitol pathway,
glucose is transformed first to sorbitol and then to fruc-
tose. This process is activated by the enzyme aldose
reductase. Although glucose is converted readily to
sorbitol, the rate at which sorbitol can be converted
to fructose and then metabolized is limited. Sorbitol is
osmotically active, and it has been hypothesized that
the presence of excess intracellular amounts may alter
cell function in the tissues that use this pathway (e.g.,
lens, kidneys, nerves, blood vessels). In the lens, for
example, the osmotic effects of sorbitol cause swelling
and opacity. Increased sorbitol also is associated with a
decrease in myoinositol and reduced ATP activity. The
reduction of these compounds may contribute to the
pathogenesis of neuropathies caused by Schwann cell
damage. Aldose reductase inhibitors have been tested
with the aim of reducing complications resulting from
this pathway; however, to date none of them has been
successful.
Formation of Advanced Glycation End Products.
Glycoproteins, or what could be called
glucose proteins,
are normal components of the basement membrane in
smaller blood vessels and capillaries. These glycopro-
teins are also termed
advanced glycation end prod-
ucts
(AGEs). It has been suggested that the increased
intracellular concentration of glucose associated with
uncontrolled blood glucose levels in diabetes favors the
formation of AGEs. These abnormal glycoproteins are
thought to produce structural defects in the basement
membrane of the microcirculation and to contribute to
eye, kidney, and vascular complications. Some of the
altered cellular functions resulting from AGEs are due
to binding to specific receptors for AGEs (RAGEs).
Protein Kinase C.
Diacylglycerol (DAG) and pro-
tein kinase C (PKC) are critical intracellular signaling
molecules that can regulate many vascular functions,
including permeability, vasodilator release, endothe-
lial activation, and growth factor signaling. Levels of
DAG and PKC are elevated in diabetes. Activation of
PKC in blood vessels of the retina, kidney, and nerves
can produce vascular damage. A PKC inhibitor was
previously studied for the treatment of diabetic reti-
nopathy and neuropathy, but showed variable results
and is not marketed.
3
Diabetic Neuropathies
Although the incidence of neuropathies is high among
people with diabetes (approximately 50% compared with
2% in the general population and approximately 15%
when age >40 years), it is difficult to document exactly
how many people are affected by these disorders because
of the diversity in clinical manifestations and because the
condition often is far advanced before it is recognized.
Results of the DCCT study showed that intensive diabetic
therapy can reduce the incidence of clinical neuropathy
by 60% compared with conventional therapy.
52
Several types of pathologic changes have been
observed in connection with diabetic neuropathies.
These include thickening of the walls of the nutrient
vessels that supply the nerve, leading to the assumption
that vessel ischemia plays a major role in the develop-
ment of these neural changes. Another finding is a seg-
mental demyelinization process that affects the Schwann
cell. This demyelinization process is accompanied by a
slowing of nerve conduction.
Although there are several methods for classifying
the diabetic peripheral neuropathies, a simplified system
divides them into the somatic and autonomic nervous
system neuropathies (Chart 33-2).
Somatic Neuropathy.
A distal symmetric polyneu-
ropathy, in which loss of function typically occurs in
a stocking–glove pattern, is the most common form of
peripheral neuropathy. Somatic sensory involvement
usually occurs first, often is bilateral and symmetric, and
is associated with diminished perception of vibration,
pain, and temperature, particularly in the lower extrem-
ities.
53
In addition to the discomforts associated with the
loss of sensory or motor function, lesions in the periph-
eral nervous system predispose a person with diabetes
to other complications. The loss of feeling, touch, and
position sense increases the risk of falling. Impairment
of temperature and pain sensation increases the risk of
serious burns and injuries to the feet. Denervation of
the small muscles of the foot result in clawing of the
toes and displacement of the submetatarsal fat pad ante-
riorly. These changes, together with joint and connec-
tive tissue changes, alter the biomechanics of the foot,
increasing plantar pressure and predisposing to develop-
ment of foot trauma and ulcers.
53
Painful diabetic neuropathy involves the somato-
sensory neurons that carry pain impulses. This disor-
der, which causes hypersensitivity to light touch and
