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ssBioMed CentCardiovascular Diabetology
Open AcceReview
Metabolic syndrome and type 2 diabetes mellitus: focus on
peroxisome proliferator activated receptors (PPAR)
Alexander Tenenbaum*1,2, Enrique Z Fisman1,2 and Michael Motro1,2
Address: 1Cardiac Rehabilitation Institute, Sheba Medical Center, 52621 Tel-Hashomer, Israel and 2Sackler Faculty of Medicine, Tel-Aviv
University, 69978 Tel-Aviv, Israel
Email: Alexander Tenenbaum* - altenen@sheba.health.gov.il; Enrique Z Fisman - zfisman@post.tau.ac.il;
Michael Motro - motrom@sheba.health.gov.il
* Corresponding author
Metabolic syndromeDiabetes mellitusPeroxisome proliferator activated receptors (PPAR)ObesityInsulin resistance
Abstract
The metabolic syndrome is a highly prevalent clinical entity. The recent Adult Treatment Panel
(ATP III) guidelines have called specific attention to the importance of targeting the cardiovascular
risk factors of the metabolic syndrome as a method of risk reduction therapy. The main factors
characteristic of this syndrome are abdominal obesity, atherogenic dyslipidemia, elevated blood
pressure, insulin resistance (with or without glucose intolerance), prothrombotic and
proinflammatory states. An insulin resistance following nuclear peroxisome proliferator activated
receptors (PPAR) deactivation (mainly obesity-related) is the key phase of metabolic syndrome
initiation. Afterwards, there are 2 principal pathways of metabolic syndrome development: 1) with
preserved pancreatic beta cells function and insulin hypersecretion which can compensate for
insulin resistance. This pathway leads mainly to the macrovascular complications of metabolic
syndrome; 2) with massive damage of pancreatic beta cells leading to progressively decrease of
insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes). This pathway leads to both
microvascular and macrovascular complications. We suggest that a PPAR-based appraisal of
metabolic syndrome and type 2 diabetes may improve our understanding of these diseases and set
a basis for a comprehensive approach in their treatment.
Type 2 diabetes mellitus and obesity, major health prob-
lems worldwide, are considered to be closely related [1–
6]. In the majority of cases type 2 diabetes is now widely
considered to be one component within a group of disor-
ders called the metabolic syndrome. Factors characteristic
of the metabolic syndrome, also known as dysmetabolic
syndrome X, are abdominal obesity, atherogenic dyslipi-
demia (elevated triglyceride [TG] levels, small low-density
lipoprotein [LDL] particles, low high-density lipoprotein
sulin resistance (with or without glucose intolerance), and
prothrombotic and proinflammatory states [7–10].
The factor that dominates in obesity is the permanent ele-
vation of plasma free fatty acid (FFA) and the predomi-
nant utilization of lipids by muscles inducing a
diminution of glucose uptake and insulin resistance. An
insulin-resistant state – as the key phase of metabolic syn-
drome – constitutes the major risk factor for the develop-
ment of diabetes mellitus. Hyperinsulinemia appears to
Published: 23 March 2003
Cardiovascular Diabetology 2003, 2:4
Received: 16 March 2003
Accepted: 23 March 2003
This article is available from: http://www.cardiab.com/content/2/1/4
© 2003 Tenenbaum et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in
all media for any purpose, provided this notice is preserved along with the article's original URL.Page 1 of 7
(page number not for citation purposes)
cholesterol [HDL-C] levels), elevated blood pressure, in- be a compensatory mechanism that responds to increased
levels of circulating glucose. People who develop type 2

Cardiovascular Diabetology 2003, 2 http://www.cardiab.com/content/2/1/4
diabetes usually pass through the phases of excessive adi-
pogenesis (obesity), nuclear peroxisome proliferator acti-
vated receptors (PPAR) modulation, insulin resistance,
hyperinsulinemia, pancreatic beta cells stress and damage
leading to progressively decrease of insulin secretion, im-
paired glucose postprandial and fasting levels [11–14].
Fasting glucose is presumed to remain normal as long as
insulin hypersecretion can compensate for insulin resist-
ance. The fall in insulin secretion leading to hyperglicemia
tients with metabolic syndrome from those with or with-
out overt diabetes (Figure 1).
Table 1 shows the diagnostic criteria for the metabolic
syndrome. The common underlying element of these ad-
verse risk factors for progression of atherosclerosis is insu-
lin resistance [10,15].
Metabolic syndrome is a term used to define a patient
Figure 1
The relationship between metabolic syndrome, insulin resistance, hyperinsulinemia and hyperglycemia (overt type 2 diabetes).
An insulin-resistant state following nuclear peroxisome proliferator activated receptors (PPAR) deactivation is the key phase of
metabolic syndrome initiation. Afterwards, there are 2 principal pathways of metabolic syndrome development: 1) With pre-
served pancreatic beta cells function and insulin hypersecretion which can compensate for insulin resistance. This pathway
leads mainly to the macrovascular complications of metabolic syndrome; 2) With massive damage of pancreatic beta cells lead-
ing to progressively decrease of insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes). This pathway leads both to
microvascular and macrovascular complications. Time-related scheme.Page 2 of 7
(page number not for citation purposes)
occurs as a late phenomenon and, in fact, separates the pa- who presents with 3 or more of 5 risk factors: (1) abdom-
inal obesity and waist circumference for men greater than

Cardiovascular Diabetology 2003, 2 http://www.cardiab.com/content/2/1/4
102 cm or 40 inches, and for women greater than 88 cm
or 35 inches; (2) elevated triglycerides, defined as equal to
or greater than 150 mg/dL; (3) low HDL cholesterol.
Overall for the Adult Treatment Panel (ATP)-III
guidelines, low HDL cholesterol is defined as under 40
mg/dL; previously it was under 35 mg/dL (for the purpos-
es of the metabolic syndrome, there are different values
for men and women: less than 40 mg/dL for men and less
than 50 mg/dL for women); (4) Elevated blood pressure,
defined according to lower values than those usually used
to define hypertension: systolic over 130 mmHg or diasto-
lic over 85 mmHg. (5) fasting glucose equal to or greater
than 110 mg/dL [10,15].
The 2001 ATP III guidelines have called specific attention
to the importance of targeting the cardiovascular risk fac-
tors of the metabolic syndrome as a method of risk reduc-
tion therapy [15]. The ATP III guidelines also call for type
2 diabetes mellitus to be given the status of "cardiovascu-
lar disease risk equivalent"; that is, patients with type 2 di-
abetes are considered to have an increased risk, equivalent
to those who have established heart disease.
Acquired causes of the metabolic syndrome include over-
weight, physical inactivity, and high carbohydrate diet in
some individuals in which the carbohydrate intake makes
up more than 60% of the total caloric intake. Moreover,
there are genetic causes, which have not been clearly de-
fined. However, our understanding of the metabolic syn-
drome has been improved by the discovery of nuclear
peroxisome proliferator-activated receptors (PPARs)
[11,12,16–18]. PPARs (Figure 2) are ligand-activated tran-
scription factors belonging to the nuclear receptor super-
family, which also includes the steroid and thyroid
hormone receptors. As transcription factors, PPARs regu-
late the expression of numerous genes and affect:
 glycaemic control
 lipid metabolism
 vascular tone
The so-called orphan receptors (identified before their
natural ligand) include PPAR and retinoid X receptors
(RXR). There are currently three known subtypes of PPAR:
alpha, delta and gamma (g1 and g2).
Activated PPAR-alpha stimulates the expression of genes
involved in fatty acid and lipoprotein metabolism. PPAR-
alpha activators, such as the normolipidemic fibric acids,
decrease triglyceride concentrations by increasing the ex-
pression of lipoprotein lipase and decreasing apo C-III
concentration. Furthermore, they increase HDL-cholester-
ol by increasing the expression of apo A-I and apo A-II.
PPAR-alpha activation by fibric acids improves insulin
sensibility and decreases thrombosis and vascular inflam-
mation. PPARalpha ligands also mediate potentially pro-
tective changes in the expression of several proteins not
involved in lipid metabolism but implicated in the patho-
genesis of heart disease. Clinical studies with bezafibrate
and gemfibrozil support the hypothesis that these drugs
may have a significant protective effect against cardiovas-
cular disease [19,20].
Activation of the isoform PPAR-gamma improves insulin
sensitivity, decreases inflammation, plasma levels of free
fatty acids and blood pressure. These lead to inhibition of
atherogenesis, improvement of endothelial function and
reduction of cardiovascular events. The thiazolidinedione
group of insulin-sensitizing drugs are PPARgamma lig-
ands, and these have beneficial effects on serum lipids in
diabetic patients and have also been shown to inhibit the
progression of atherosclerosis in animal models. Howev-
er, their efficacy in the prevention of cardiovascular-asso-
ciated mortality has yet to be determined.
Recent studies have found that PPAR delta is also a regu-
lator of serum lipids. However, there are currently no
drugs in clinical use that selectively activate this receptor.
The modulation of the expression of genes by either PPAR
alpha or gamma activators, correlates with the relatively
tissue-specific distribution of the respective PPARs: PPAR
gamma is expressed predominantly in adipose tissues,
whereas PPAR alpha in the liver.
Table 1: Diagnostic Criteria for the Metabolic Syndrome [10,15]
Abdominal obesity (waist circumference >102 cm [40 in] in men, >88 cm [35 in] in women)
Hypertriglyceridemia (>/= 150 mg/dL)
Low HDL-C (< 40 mg/dL in men, <50 mg/dL in women)
High blood pressure (>/= 130/85 mm Hg)
High fasting glucose (IGT [blood sugar >/= 110 mg/dL and <126 mg/dL] without diabetes)Page 3 of 7
(page number not for citation purposes)
 inflammation.

Cardiovascular Diabetology 2003, 2 http://www.cardiab.com/content/2/1/4
PPARgamma was shown to have a key role in adipogene-
sis and proposed to be a master controller of the "thrifty
gene response" leading to efficient energy storage. Accord-
ing to the thrifty gene hypothesis, individuals living in an
environment with an unstable food supply could increase
their probability of survival if they could maximize stor-
age of surplus energy, for instance as abdominal fat. Ex-
posing this energy-storing genotype to the abundance of
food typical in western societies is detrimental, causing in-
sulin resistance and, subsequently, type 2 diabetes
[11,21]. In addition to PPAR, there are a number of other
potential thrifty genes, including those that regulate lipol-
ysis or code for the beta3-adrenergic receptor, the hor-
mone-sensitive lipase, and lipoprotein lipase. Type 2
More recently PPARgamma emerged from a role limited
to metabolism (diabetes and obesity) to a power player in
general transcriptional control of numerous cellular proc-
esses, with implications in cell cycle control, carcinogene-
sis, inflammation, atherosclerosis and
immunomodulation. This widened role of PPAR gamma
will certainly initiate a new flurry of research, which will
not only refine our current (and often partial) knowledge
of PPARgamma, but more importantly, will also establish
that this receptor has a definite role as a primary link
adapting cellular, tissue and whole body homeostasis to
energy stores.
Based on these new concepts, we propose a novel map of
Figure 2
The peroxisome proliferator activated receptors (PPARs) in the framework of the nuclear receptors superfamily.Page 4 of 7
(page number not for citation purposes)
diabetes develops as a consequence of a collision between
thrifty genes and a hostile affluent environment.
a cluster of metabolic syndrome, cardiovascular risk

Cardiovascular Diabetology 2003, 2 http://www.cardiab.com/content/2/1/4
factors and diseases, which all are developed and linked
through PPARs (Figure 3).
Because of its critical and central role in the development
of metabolic syndrome, type 2 diabetes and many cardio-
vascular disorders, we believe that targeted treatment of
PPAR will be a critical component of care in shortcoming
future (Figure 4). Treating metabolic syndrome can pre-
vent or ameliorate cardiovascular disease and type 2 dia-
betes [22–27]. It is obvious that the cornerstones of
treatment for the metabolic syndrome are dietary modifi-
individualized, systematic and intensive lifestyle interven-
tions (including dietary changes, increased physical activ-
ity and weight loss) are the most effective means of
prevention of type 2 diabetes in general high risk
populations (unfortunately they are not easily applied in
general practice) [24]. Pharmacological interventions by
some medications which influence primary glucose me-
tabolism (metformin and acarbose) or induced weight
loss (orlistat, combined with dietary intervention) can
also effectively delay progression to type 2 diabetes [24–
26], but the magnitude of the benefit seems to be some-
Figure 3
The atherogenesis tree, showing the complex interrelationship between hereditary and environmental factors in the pathogen-
esis of metabolic syndrome and atherothrombotic events. The central role of an insulin-resistant state following adipogenesis
and nuclear peroxisome proliferator activated receptors (PPAR) deactivation is emphasized. CAD – coronary artery disease;
AP – angina pectoris; ACS – acute coronary syndromes; CHF – congestive heart failure; PVD – peripheral vascular disease;
HDL – high density lipoproteins cholesterol; IGT – impaired glucose tolerance; IFG – impaired fasting glucose.Page 5 of 7
(page number not for citation purposes)
cation and increased physical activity. The Diabetes Pre-
vention Program (DPP) results have shown that
what less (58% for DPP lifestyle changes vs. 31% for met-
formin and 25% for acarbose). For the time being, the

Cardiovascular Diabetology 2003, 2 http://www.cardiab.com/content/2/1/4
goals and methods of treating hypertension, inflamma-
tion, hypercoagulopathy and dyslipidemia are the same
for people with metabolic syndrome and for the general
population [22–27].
In conclusion, the metabolic syndrome is a highly preva-
lent clinical entity. Obesity, PPAR modulation and insulin
resistance are the central components of this complex syn-
drome. The fall in insulin secretion leading to hypergli-
cemia separates patients with metabolic syndrome from
those with or without overt diabetes. We suggest that a
PPAR-based appraisal of metabolic syndrome and type 2
diabetes may improve our understanding of these diseases
and set a basis for a comprehensive approach in their
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