14
Adipocytes
because of the dramatic rise in the preva-
lence of these related disorders. Although
the causal relationship between diabetes
and obesity is not fully understood, a likely
common link is the adipocyte. Given that
adipose tissue serves to buffer excess lipid,
and to confer insulin resistance that is as-
sociated with inappropriate accumulation
of lipid in nonadipose cells, it is not sur-
prising that the dysfunction in adipose
tissue could profoundly affect diabetes sus-
ceptibility. The inability of adipose tissue
to buffer circulating lipid levels and con-
current accumulation of lipid in muscle
and liver may, in fact, be an early event in
the development of diabetes. This poten-
tial link between adipose tissue function
and diabetes raises the new and excit-
ing possibilities for the development of
therapeutic agents to treat diabetes. Drugs
targeted to very speciFc metabolic or hor-
monal functions in the adipocyte could
potentially have a profound beneFcial ef-
fects on metabolism throughout the body.
Thefollowingisasummaryoftheknown
defects in adipose function and their ef-
fects on energy metabolism and glucose
homeostasis. We will also review what is
known about the antidiabetic thiazolidine-
dione drugs that are thought to have their
effects by modifying adipocyte physiology.
4.1
Obesity – Too Much Fat
A long-standing observation in the Feld of
diabetes research is that obese individu-
als have an increased risk of developing
insulin resistance and type 2 diabetes.
The current epidemic of diabetes in west-
ern cultures began about thirty years ago
and correlates precisely with the concur-
rent explosion of obesity. This has led
to the assumption that there is a func-
tional, or causative relationship between
these two disorders; that the presence of
obesity increases susceptibility to diabetes.
Although the relation between these two
metabolic disorders is unmistakable, it is
not understood how obesity precipitates
the multiple functional defects that pre-
cede overt diabetes. However, an emerg-
ing candidate is the acquired inability of
adipocyte to protect important tissues and
cells throughout the body from exposure
to excessive lipids.
No
rma
l
ly
,excessca
lo
r
iesa
res
to
redin
the body in the form of triglycerides,
mainly in adipocytes of white fat tissue.
However, nonadipocyte cells also store
low levels of triglycerides to meet in-
ternal metabolic requirements. In these
cells, the amount of stored triglyceride is
maintained within a very narrow range.
A fatty acid homeostatic system functions
in healthy individuals to direct excess fat
to adipocytes while maintaining normal
amounts of triglyceride in nonadipocytes.
Under conditions of chronic positive en-
ergy balance and ensuing obesity, however,
the capacity for adipose tissue to buffer
excess lipid energy may be exceeded, re-
sulting in the pathological accumulation
of lipid within key metabolic tissues.
The elevation of free fatty acid (±±A) in
the blood is predictive of conversion from
impaired glucose tolerance to diabetes,
suggesting that ±±A themselves could con-
tribute to organ defects that precede type
2 diabetes, such as insulin resistance of
skeletal muscle, and reduced pancreatic
insulin secretion. More recently, it has
been shown that intracellular accumu-
lation of lipid within myocytes strongly
predicts insulin resistance
independent of
the magnitude of obesity
. Thus, it is not the
accumulation of lipid in fat cells
per se
that
is problematic, rather it is the redirection
of lipid to other key cells that occurs once
the capacity of the adipocyte to handle
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