Effect of Insulin Resistance, Dyslipidemia, and
Intra-abdominal Adiposity on the Development of
Cardiovascular Disease and Diabetes Mellitus
Daniel J. Rader, MD
Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Abdominal obesity contributes to insulin resistance, a metabolic abnormality linked to the development of
type 2 diabetes mellitus and cardiovascular disease (CVD). Insulin resistance generally precedes the
development of type 2 diabetes. Currently, an estimated 10 million US adults have diabetes and another
25 million have impaired glucose tolerance (IGT), an intermediate step between insulin resistance and
diabetes. The pathophysiologic mechanisms known to increase CVD risk in individuals with insulin
resistance include formation of advanced glycation end products, hypertension, proinflammatory and
prothrombotic states, and dyslipidemia (i.e., low levels of high-density lipoprotein cholesterol, increased
levels of triglycerides, small, dense low-density lipoprotein cholesterol particles, apoplipoprotein B, and
inflammation). The increased flux of free fatty acids from adipose tissue to the liver promotes dyslipidemia.
Insulin resistance and impaired glucose tolerance are associated with increased CVD risk. Individuals with
coexisting metabolic syndrome and diabetes have the highest prevalence rates of CVD. The Nurses’ Health
Study showed that CVD risk was elevated even before the development of diabetes compared with women
who never developed diabetes. Lifestyle modification is recommended as the first-line treatment for obesity
alone are ineffective or insufficient. Primary care physicians play a critical role in the early identification and
treatment of patients at increased risk for the development of type 2 diabetes and CVD because of their obesity
and associated complications. © 2007 Elsevier Inc. All rights reserved.
Cardiovascular disease; Impaired glucose tolerance; Insulin resistance; Metabolic syndrome; Type 2
The prevalence of obesity, type 2 diabetes mellitus, and the
metabolic syndrome has increased dramatically in the past 2
decades.1,2Obesity, specifically visceral abdominal obesity,
contributes to the development of insulin resistance, which
may underlie a number of the manifestations and cardio-
vascular complications of diabetes and the metabolic syn-
drome.3Insulin resistance is associated with increased car-
diovascular risk as well as the risk for developing overt
diabetes. Therefore, early intervention to treat insulin resis-
tance is an important preventive health strategy.
PATHOPHYSIOLOGY OF INSULIN RESISTANCE
Although it is recognized that insulin resistance increases
the risk for type 2 diabetes, it is not as well known that it
also increases the risk for cardiovascular disease (CVD).4–6
A number of factors increase the risk for insulin resistance,
including genetic predisposition, obesity and inactivity, ag-
ing, medications, polycystic ovary syndrome, and rare dis-
orders such as partial lipodystrophy.7Concomitant condi-
tions that are associated with insulin resistance include type
2 diabetes, hypertension, dyslipidemia, atherosclerosis, and
polycystic ovarian syndrome (Figure 1).
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The American Journal of Medicine (2007) Vol 120 (3A), S12–S18
resistant states are associated with a particular dyslipidemic
profile characterized by hypertriglyceridemia, low levels of
HDL cholesterol, and small, dense LDL cholesterol parti-
cles. The increased flux of free fatty acids from adipose
tissue to the liver exacerbates hepatic insulin resistance and
promotes all of these aspects of dyslipidemia. CVD risk
increases markedly as glycemic abnormalities (i.e., insulin
resistance and IGT) progress to overt diabetes.
Lifestyle modifications (diet and exercise) that target
weight reduction, especially reduction in abdominal adipos-
ity, comprise the first-line approach to treating glycemic
abnormalities and reducing the risk for diabetes and CVD.
Pharmacologic therapy is used adjunctively in patients at
higher risk and those recalcitrant to lifestyle modification.
Primary care physicians can play a major role in the early
identification and preventive management of insulin-resis-
tant states to help reduce progression to type 2 diabetes and
decrease the risk for CVD.4
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S18The American Journal of Medicine, Vol 120 (3A), March 2007