Insulin Resistance and Obesity
JERRY R. GREENFIELD, MD
LESLEY V. CAMPBELL, MD
Abstract. Obesity, particularly central obesity, is associated with insulin resistance. Much research has focused on mechanisms
that link obesity to insulin resistance, including lipid accumulation in muscle and liver and the recently discovered adipocytokines.
Insulin resistance is an important feature of a number of common conditions, including type 2 diabetes and polycystic ovary
syndrome and is associated with rarer disorders, such as inherited insulin receptoropathies and genetic and acquired lipodystro-
phies. Despite its use for a number of years, metformin’s role as an insulin sensitizer has only recently been appreciated. The
discovery of a new class of insulin sensitizing agents, the thiazolidinediones, represents a major advance in the understanding of
the etiology of insulin resistance, particularly in relation to adipocyte biology and possibly, its inflammatory origins.
I
nsulin resistance, or an attenuated biological re-
sponse to insulin, is a core component of the “met-
abolic syndrome.” In addition to insulin resistance,
other metabolic components of the syndrome include
central abdominal obesity, “diabetic dyslipidemia”
(low high-density lipoprotein cholesterol, high triglyc-
eride levels, and small, dense low-density lipoprotein
cholesterol), glucose intolerance, type 2 diabetes melli-
tus, and hypertension.
1
The importance of identifying
and treating this cluster of metabolic abnormalities re-
lates not only to its relationship with type 2 diabetes
mellitus, but also to the significantly increased risk of
atherothrombotic cardiovascular disease associated
with it.
1
The strong association between obesity (partic
-
ularly central abdominal obesity) and impaired insulin
action, is the focus of this article, in which we discuss
the insulin- signalling pathway, the molecular mecha-
nisms of insulin resistance, including the recent interest
in adipocytokines, specific congenital and acquired in-
sulin-resistance syndromes and therapy of insulin re-
sistance, with particular reference to polycystic ovary
syndrome (PCOS).
The Insulin-Signalling Cascade
Insulin is an important metabolic hormone synthesized
by pancreatic  cells, which stimulates glucose uptake
in various organs, particularly muscle, adipose tissue,
and the liver, and inhibits lipolysis in adipose tissue.
The initiating step in the insulin-signalling cascade is
the binding of insulin to the insulin receptor on the
plasma membrane of insulin-sensitive tissues. The in-
sulin receptor is a large transmembrane heterotet-
rameric receptor (␣
2

2
) comprising two insulin-binding
extracellular ␣ subunits and two predominantly intra-
cellular  subunits (Fig 1).
2
Insulin binding to the ␣
subunits results in activation of an intrinsic tyrosine
kinase, receptor autophosphorylation and phosphory-
lation of insulin receptor substrates (IRSs), including
IRS-1, a key protein in the insulin-signalling pathway
(Fig 1).
3,4
This leads to a cascade of intracellular events,
including activation of the enzyme phosphatidylinosi-
tol-3 (PI-3) kinase, culminating in translocation of the
glucose transporter GLUT-4 from intracellular vesicles
to the plasma membrane, increased glucose uptake into
the cell, and a number of other changes in enzyme
activity predominantly directed toward increased syn-
thesis or reduced breakdown of glycogen and triglyc-
eride.
3
Metabolic Links Between Obesity and
Insulin Resistance
A major body of research has focused on identifying
specific defects in the insulin-signalling cascade that
impair insulin-mediated glucose uptake, including the
mechanisms by which lipid oversupply to insulin-sen-
sitive tissues may lead to insulin resistance. The accu-
mulation of fat in the abdominal region is thought to be
a critical determinant of whole-body insulin resistance.
5
In contrast to peripheral adipose tissue, which appears
to not be associated with adverse metabolic conse-
quences and may even be protective, central abdominal
fat is a more labile fat depot, from which fatty acids
drain directly into the portal system; in addition, lipol-
ysis in central abdominal adipocytes is less suppressible
by insulin.
6,7
Using the hyperinsulinemic-euglycemic
clamp to directly measure insulin sensitivity in vivo, we
have shown that central abdominal fat is a stronger
determinant of insulin resistance than total body, limb,
or trunk fat in normal and overweight women.
5
It is widely accepted that the accumulation of fatty
acids in insulin-sensitive nonadipose tissues, such as
muscle and liver, can impair insulin-mediated glucose
From the Diabetes and Obesity Research Program, Garvan Institute of
Medical Research, Sydney, Australia and the Diabetes Centre, St. Vincent’s
Hospital, Sydney, Australia.
Address correspondence to Dr. Jerry Greenfield, Garvan Institute of
Medical Research, 384 Victoria St., Darlinghurst 2010, Australia.
E-mail address: j.greenfield@garvan.org.au
© 2004 by Elsevier Inc. All rights reserved. 0738-081X/04/$–see front matter
360 Park Avenue South, New York, NY 10010 doi:10.1016/j.clindermatol.2004.01.011