21

Dyslipidemia
in the Metabolic Syndrome
MARKOLF HANEFELD AND FRANK SCHAPER
CENTER OF CLINICAL STUDIES, TECHNICAL UNIVERSITY, DRESDEN, GERMANY

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Resumen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
The lipid triad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Dyslipidemia profile in the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
Pathophysiology of metabolism of triglyceride rich lipoproteins (TRLs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
Dyslipidemia in the Metabolic Syndrome primarily a postprandial phenomenon? . . . . . . . . . . . . . . . . . . . . . . . 352
Dyslipidemia and insulin resistance in the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
Dyslipidemia and vascular disease in the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
348 • Related Diseases in the Metabolic Syndrome

Summary
Dyslipidemia is a central component of the Metabolic Syndrome. In the WHO and in the NCEP-ATPIII definitions low HDL and hyper-
triglyceridemia are considered as one and two separated traits respectively. Hypertriglyceridemia, low HDL-chloesterol and small,
dense LDL -called the lipid triad- are present in 40-50% of the patients with the Metabolic Syndrome. However the dyslipidemia of the
Metabolic Syndrome is more complex, comprising anomalies in fatty acids regulation and changes in the pattern and composition of
triglyceride-rich proteins as well as in HDL-cholesterol and LDL subfractions. The increase in the triglyceride content of LDL increases
the length of their exposure to oxidation and glycation, increasing their atherogenicity. Anomalies in visceral fat cell metabolism and in-
sulin resistance are mayor players in the underlying pathophysiology. Disturbances in VLDL synthesis and in the removal of triglyc-
eride-rich lipoproteins are first observed in the postprandial phase, before type 2 diabetes is diagnosed. Type 2 diabetes amplifies the
functional and structural changes in lipoprotein metabolism. Dyslipidemia is a prominent risk factor for both diabetes and atheroscle-
rosis. However the full cluster of the Metabolic Syndrome confers higher risk. This speaks in favor of the hypothesis that dyslipidemia
acts together with the other risk factors (diseases of the Metabolic Syndrome) in a vicious cycle. Early signals from prospective studies
indicate that the strict correction of dyslipidemia may be an option for primary and secondary prevention of cardiovascular diseases
and type 2 diabetes.

Resumen
La dislipidemia es un componente central del síndrome metabólico. Tanto en la definición de la OMS (WHO) como en la que el
NCEP-ATPIII hacen del síndrome metabólico, niveles bajos de colesterol-HDL y elevados de triglicéridos son considerados como
uno solo o dos rasgos independientes. Hipertrigliceridemia, colesterol-HDL bajo y la presencia de particulas de LDL densas y pe-
queñas –la llamada tríada lipídica– se encuentran en el 40 a 50% de los pacientes con síndrome metabólico. Sin embargo, la dis-
lipidemia del síndrome metabólico es más compleja e incluye alteraciones en la regulación de los ácidos grasos libres y cambios
en el patrón y composición de las proteínas enriquecidas con triglicéridos, así como también en las subfracciones de colesterol-
HDL y de LDL. El incremento en el contenido de triglicéridos de las LDL aumenta su exposición a los procesos de oxidación y
glicación, aumentando así su aterogencidad. Anomalías metabólicas en las células de la grasa visceral junto con la insulino-re-
sistencia juegan un papel sumamente importante en la fisiopatología subyacente. En el estado postprandial, aun antes de que se
haya diagnosticado una diabetes tipo 2, se observan alteraciones en la síntesis de VLDL y en la eliminación de la circulacion de
proteínas ricas en triglicéridos. La presencia de diabetes tipo 2 amplifica los cambios estructurales y funcionales en el metabo-
lismo de las lipoproteínas. La dislipidemia es un importante factor de riesgo tanto para el desarrollo de la diabetes como para el
de enfermedades cardiovasculares. Sin embargo, el síndrome metabólico, como un todo, se asocia con un riesgo mayor. Este he-
cho favorece la hipotésis de que los varios componentes (factores de riesgo) del síndrome metabólico actúan conjuntamente con
la dislipidemia, en un círculo vicioso. Datos recientes, provenientes de estudios clínicos prospectivos, señalan que la corrección
estricta de la dislipidemia podría ser una opción para la prevención primaria y secundaria de las enfermedades cardiovasculares
y de la diabetes tipo 2.

Elevated levels of lipids have been long associated with

the Metabolic Syndrome. Already in 1981 we defined the
Metabolic Syndrome as follows: “By this term, we un-
derstand the simultaneous occurrence of obesity, hyper-
and dyslipoproteinemia, maturity onset diabetes (type II),
gout, and hypertension, associated with an elevated
incidence of atherosclerotic vascular diseases, fatty liver,
and gallstones in overfed, physically inactive and genet-
ically predisposed people”1 (Fig. 21-1).
Recent investigations have confirmed that dyslipi-
demia is a key trait of the Metabolic Syndrome either with
or without diabetes. The importance of dyslipidemia as
both a risk factor for type 2 diabetes and coronary heart
disease (CHD) is acknowledged in the two most recent
and widely used definitions. The WHO definition (Ta-
ble 21-1)2 takes into account that insulin resistance may be
the unifying common soil underlying the traits of the Meta-
bolic Syndrome. While in the WHO definition the hyper-
Table 21-1. Definition of the Metabolic
Syndrome: WHO 1999 proposal
A person with type 2 diabetes or IFG/IGT has the
Metabolic Syndrome if two of the criteria listed below
are fulfilled. A person with NGT has the Metabolic
Syndrome if he/she fulfils two of the criteria in addition
to being insulin resistant. Insulin resistance is defined as
the highest quartile of the HOMA insulin resistance
index.
Components of the Metabolic Syndrome
1. Hypertension defined as antihypertensive treatment
and/or blood pressure ≥140-90 mmHg
2. Dyslipidemia defined as elevated plasma triglyceride
(≥1.7 mmol/l) and/or low HDL cholesterol (<0.9 mmol/l
in men; <1.0 mmol/l in women) concentrations
3. Obesity defined as high BMI (≥30 kg/m2) and/or high
waist hip ratio WHR >0.90 in males, >0.85 in women
and
4. Microalbuminuria (urinary albumin excretion rate
≥20μg/min).

HLP
Hyper
lipoproteinemia
ia
sulinem
NIDDM Gout
ophilia
Atheros-
erin
mb
clerosis
yp
ro
Th H terol. The dyslipidemia observed in these high risk pa-
Obesity Hypertension
Overnutrition
Lack of Physical Excercise
Sociocultural Factors
Genetic Predisposition
Figure 21-1. The Metabolic Syndrome1.
triglyceridemia/low HDL combination is considered to
be one single trait. Thus, the WHO definition presents a
mix of pathophysiology, risk factors and diseases. In the
National Cholesterol Education Program – Third Adult
Treatment Panel (NCEP-ATPIII) definition (Table 21-2)3
low HDL-cholesterol and hypertriglyceridemia are two
separate traits. In order to make a diagnosis of the Meta-
bolic Syndrome according to NCEPIII criteria, a patient
must suffer from three or more of the five risk factors
shown in Table 21-2. All the cut-off limits including those
for dyslipidemia are arbitrary and need to be confirmed
by prospective studies. In 2005 the International Diabetes
Federation will hold a symposium in Berlin on predia-
betes and the Metabolic Syndrome, with the aim of reach-
ing a consensus for a new and unifying definition, which
should also be accepted by the WHO. The concept of the
Metabolic Syndrome opens the glucocentric view of type
2 diabetes as well as the lipocentric view of atheroscle-
rotic vascular disease (AVD) for an integrated approach
in diagnostics and prevention. Thus, there is more and
more evidence that the traits of the Metabolic Syndrome
such as dyslipidemia, visceral obesity, non-alcoholic, fat-
ty liver and hypertension share a common soil with in-
sulin resistance and anomalies of fatty acid metabolism
as major players. As shown in the previous chapters the
Metabolic Syndrome can also be given the status of “car-
diovascular risk equivalent”4-6.
This chapter will analyze (1) the epidemiology of dys-
lipidemia as a trait of the Metabolic Syndrome (2), the in-
teraction of insulin resistance with comorbidities such as
Dyslipidemia in the Metabolic Syndrome • 349
visceral obesity and impaired glucose regulation (3), and
the importance of dyslipidemia as a cause of endothelial
dysfunction and as a risk factor for AVD within the
frame of the Metabolic Syndrome.
The lipid triad
The diagnostic of anomalies in circulating lipids in the
Metabolic Syndrome is primarily based on the measure-
ment of triglycerides, HDL-cholesterol and LDL-choles-
tients is characterized by the lipid triad: hypertrigly-
ceridemia, low HDL-cholesterol and increase in small,
dense low density lipoprotein (LDL) particles (LDL pat-
tern B, LDLIII) with total and LDL–cholesterol levels in
the average range or slightly elevated. The small dense
LDL subfraction is highly atherogenic7. Thus LDL parti-
cles bear an increased atherogenic risk compared with
those from a subject without the Metabolic Syndrome
and the same level of LDL-cholesterol.
Epidemiology: The Metabolic Syndrome is highly
prevalent in the population of western countries compro-
mising not less than 20-45% of the population older than
40 years, as shown in studies from the US8, Germany9 and
the Scandinavian countries10 However, also in developing
countries like China, which has rapidly adapted to
Western life-style, a high prevalence of the Metabolic Syn-
drome can be observed11. Considering single traits, the
prevalence of dyslipidemia varies depending on age, race,
life-style and selection criteria, for example exclusion of
subjects with AVD or drugs affecting lipid metabolism.
There are only few population-based studies which
present data on the percentage of people with dyslipi-
demia according to WHO criteria or with hypertrigly-
ceridemia or low HDL-cholesterol according to NCEPIII
criteria8-12.
More information exists on the prevalence and combin-
ations of dyslipidemia in high risk populations. The
Botnia study13 is a prospective family study in two Nordic
Table 21-2. Definition of the Metabolic
Syndrome as defined by NCEPIII
Three or more of the following criteria:
1. Abdominal obesity: waist circumference >102 cm in
men and >88 cm in women
2. Hypertriglyceridemia: ≥150 mg/dL (1.69 mmol/l)
3. Low high-density lipoprotein (HDL) cholesterol:
<40 mg/dL (1.04 mmol/l) in men
<50 mg/dL (1.29 mmol/l) in women
4. High blood pressure: ≥130/85 mmHg
5. High fasting glucose: ≥110 mg/dL (≥6.1 mmol/l)
350 • Related Diseases in the Metabolic Syndrome

Table 21-3. Prevalence of the Metabolic Syndrome and its different components in male
and female subjects with NGT, abnormal IFG/IGT and diabetic glucose
tolerance13

NG IFG/IGT TYPE 2 DM
All 35-70 Male Female Male Female Male Female
years
Metabolic 15 10 64 42 84 78
syndrome
Obesity 76 36 86 51 92 78
Dyslipidemia 29 16 45 31 54 56
Hypertension 23 24 31 35 55 59
Micro 4 3 7 6 22 12
albuminuria
Insulin 25 25 58 59 87 89
Resistance
Data are %

countries. The aim of the study was to identify metabolic
abnormalities in families with type 2 diabetes. Glucose
tolerance was assessed according to WHO criteria using
75 g OGTT. The prevalence of the Metabolic Syndrome
(WHO definition) and of its single traits by sex and cate-
gory of glucose tolerance is given in Table 21-3. The most
frequent combinations were obesity and dyslipidemia,
followed by hypertension and dyslipidemia.
In the Risk Factors in IGT of Atherosclerosis and
Diabetes (RIAD) study using NCEPIII criteria hyper-
triglyceridemia and low HDL were found as single traits
in 20-40% of the population (Table 21-4)14. The increment
in the parameters of the lipid triad starts far before dia-
betes is diagnosed (Fig. 21-2). Both studies showed a
stepwise increase in dyslipidemia from normal glucose
tolerance to newly detected type 2 diabetes with a sig-
nificantly higher prevalence in the female sex with nor-
mal glucose tolerance and impaired fasting glucose/im-
paired glucose tolerance.
In the Bothnia study 10% of the patients with normal
glucose tolerance, about 50% of the subjects with predi-
abetes (IFG/IGT) and about 80% of the patients with
type 2 diabetes suffered from the Metabolic Syndrome
according to the WHO definition.

Dyslipidemia profile in
7 the Metabolic Syndrome
6
Lipid abnormalities in these high risk
mean values (mmol/l)

5 populations are complex and reach far

beyond the lipid triad (Table 21-5).
4
**
Most data on dyslipidemia and the
3 Metabolic Syndrome correspond to ab-
*
normalities in type 2 diabetes and pre-
2 * * diabetic hyperglycemia15-16. Increases
1 in free fatty acids (FFA) and in the con-
0 centration and composition of circulat-
2.70 – 5.43 5.44 – 6.39 6.40 – 7.76 7.77 – 9.33 9.34 – 23.12 ing lipoproteins start before diabetes is
(mmol/l) diagnosed in the stages of IFG and IGT.
quintiles of 2hpp plasma glucose

* p < 0.05 comparing to 1st, 2nd and 3rd quintile

HDL-C
** p < 0.05 comparing to 1st, 2nd, 3rd and 4th quintile
triglycerides Figure 21-2. Plasma lipid levels by quintiles
total cholesterol
of 2 hs. postchallenge plasma glucose levels
in a high risk-population without known
diabetes: The RIAD study.
 Dyslipidemia in the Metabolic Syndrome • 351

Table 21-4. Prevalence of diseases in the categories of glucose intolerance associated

and type 2 diabetes: the RIAD study

NGT IFG IGT DM RR RR

DM/NGT IGT/NGT
Obesity* 26.8 40.5 43.0 45.9 2.3 2.1
(1.6...3.3) (1.6...2.8)
Hypertension* 25.1 35.9 41.3 47.7 2.7 2.1
(1.9...3.9) (1.6...2.8)
Dyslipoproteinemia* 27.1 29.0 32.6 43.0 2.0 1.3
(1.4...2.9) (1.0...1.7)
Coronary heart 13.6 19.1 17.4 15.7 1.2 1.3
disease§ (0.7...1.9) (1.0...1.7)
* signif. difference NG vs. IGT/DM (p < 0 .001) with ?≤-Test; § according to medical history, NGT: normal glucose tolerance

Forty years ago Randle et al.17 demonstrated that in-
creased availability of fatty acids decreased glucose
oxidation and glucose uptake in the perfused rat´s
heart. Based on these findings they proposed a glucose-
fatty acid cycle presumed to be of fundamental impor-
tance for the control of blood glucose and insulin sen-
sitivity in subjects with and without diabetes. As
shown by Reaven et al.18 FFA and insulin levels are in-
creased in obese patients with type 2 diabetes. In vivo
elevated FFA have been shown to enhance hepatic glu-
cose and triglyceride production19. Long-term increase
of FFA may also inhibit insulin secretion (lipotoxici-
ty)20. In an elegant review of the evidence supporting
a central role for the anomalies in lipid metabolism in
the development of type 2 diabetes entitled “What if
Minkowski had been ageusic? An alternative angle on
diabetes” McGarry came to the conclusion that anom-
alies in fatty acid regulation and triglyceride-rich
lipoproteins may play a central role in the develop-
Pancreas
? + + eridemia in type 2 diabetes and in
Hyperinsulinemia
(Hyperamylinemia?)
Liver
VLDL triglycerides
Adipose tissue
Fat deposition (early) Triglyceride and fatty acids
FFA reesterfication (later) Glycogen synthesis
+
Plasma FFA
ment of type 2 diabetes and diseases of the Metabolic
Syndrome21 (Fig. 21-3).
Pathophysiology of metabolism
of triglyceride rich lipoproteins (TRLs)
Increases in triglyceride rich lipoproteins and changes in
their composition are typical of the Metabolic Syndrome
with and without diabetes. Postprandial hyperlipidemia
is frequently found in subjects with IGT and type 2 dia-
betes22-24. This strongly depends on fasting triglyceride
levels25. The postprandial excursion of chylomicrons is
elevated and lasts longer in subjects with dyslipidemia
and other traits of the Metabolic Syndrome.
Very low density lipoproteins (VLDL) are produced
by the liver depending on the flow of free fatty acids
from visceral fat depots, insulin sensitivity to hepatic
glucose and triglyceride synthesis26 (Fig. 21-4). VLDL
particles can be separated into two major subclasses:
large buoyant VLDL1 and smaller,
denser VLDL2. It is a consistent find-
ing that the fasting hypertriglyc-
the Metabolic Syndrome is mainly
due to an increase in VLDL126. The
elevation of VLDL1 has serious con-
sequences for TRL catabolism: the
production of slowly metabolised
LDL leads to the generation of small
Muscle
dense LDL with a prolonged half-life
time. This is presumed to promote
Glucose oxidation oxidation and glycosylation of apo B
Insulin resistance
in lipoprotein remnants and LDL.

Glucose intolerance Figure 21-3. Importance of anomalies

in fatty acid regulation and metabolism
b–Cell failure +
of triglyceride-rich lipoproteins for the
NIDDM development of insulin resistance and type 2
diabetes21.
352 • Related Diseases in the Metabolic Syndrome

monal and metabolic regulation occur first in the post-

TG
prandial phase. This is obviously also valid for dyslipi-
VLDL HDL
CE
demia. Recently a bulk of epidemiological studies have
been published suggesting that postprandial/postchal-
CETP lenge glucose excursions are a risk factor for AVD in its
TG CE
own right31,33. Fat intolerance is a distinct component of
CE TG dyslipidemia in the Metabolic Syndrome25 and it is close-
ly correlated to postprandial glucose excursion and in-
LDL sulin resistance (Fig. 21-5). However, the peak in triglyc-
HTGL eride levels after a fat load is not higher and the 4-6-hour
concentrations in individuals with IGT and type 2 dia-
Dense LDL betes are not different from those of subjects with NGT
when these subjects are compared to subjects with nor-
mal fasting triglycerides.
Figure 21-4. Pathophysiology of dyslipidemia in the
Metabolic Syndrome. Therefore, in real life, patients with the Metabolic Syn-
drome, IGT and type 2 diabetes who present lipid intol-
erance are exposed to high triglyceride concentrations
The co-existence of these changes in the composition of 24 hours a day34.
LDL strongly increases the atherogenicity of the small In a recent review26 M.R. Taskinen came to the con-
dense LDL. There is a stepwise increase in the forma- clusion that about 80% of increase in postprandial TRL
tion of small dense LDL in relation to triglyceride lev- is due to VLDL and only 20% to chylomicrons, with an
els in type 2 diabetes27. Interestingly, the percentage of
small dense LDL subclass is already increased in nor-
motriglyceridemic subjects with type 2 diabetes. It is an
180
open question how does the combination of different R = 0.344
traits of the Metabolic Syndrome contribute to alter- 160 p = 0.006

ation in TRL metabolism. Another consequence of hy-

AUC - PG (mmol/l*6h)

140
pertriglyceridemia is triglyceride enrichment of HDL 120
particles, particularly of HDL2. This chemical modifica-
100
tion enhances the catabolism of HDL in people with28 DM
type 2 diabetes. 80
This is even the case in subjects with normal glucose 60 IGT

tolerance. If HDL becomes triglyceride-enriched29, as 40 NGT

shown in a kinetic study with stable isotopes in subjects
20
with IGT, the increase in HDL catabolic rate is the un- 0 10 20 30 40 50
derlying pathophysiology for low HDL-cholesterol lev- AUC - TG (mmol/l*6h)
els in this prediabetic category of glucose intolerance30.
There are two key enzymes involved in TRL and HDL 160
R = 0.433
catabolism: lipoprotein lipase and hepatic triglyceride li- 140 p < 0.001
Insulin resistance (HOMA)

pase. Both enzymes are closely connected to insulin se- 120

cretion and insulin sensitivity. Hepatic lipase is positive-
100
ly and lipoprotein lipase inversely correlated to the
triglyceride content of HDL. Thus the underlying patho- 80
DM
physiology of the Metabolic Syndrome interacts in a 60
very complex way with the lipoprotein metabolism in 40 IGT
subjects with and without type 2 diabetes.
20 NGT

0
Dyslipidemia in the Metabolic Syndrome 0 10 20 30 40 50
primarily a postprandial phenomenon? AUC-TG mmol/l/6h

The Metabolic Syndrome may be considered to develop as Figure 21-5. Relationship between postprandial triglycerides,
an initial postprandial disease since alterations in hor- glucose excursions and insulin resistance25.

excess of VLDL1. Thus circulating triglycerides are
mainly derived from hepatic triglyceride production
rather than from the intestinal lipid pool. This suggests
a major role for visceral fat, insulin resistance and li-
pases in the pathogenesis and severity of dyslipidemia
in the Metabolic Syndrome. Again, little is known on
the impact of the single traits of the Metabolic Syn-
drome on postprandial hyperlipidemia. From our in-
vestigations in people with IGT it looks as if, in care-
fully selected men with normal fasting triglycerides,
IGT and type 2 diabetes, if well controlled, did not es-
calate postprandial triglyceride excursion25. There is no
evidence that fat intolerance precedes glucose intoler-
ance, whereas increased levels of fasting triglycerides
obviously deteriorate insulin sensitivity and lipid tol-
erance.
The reasons for excessive postprandial lipidemia are
complex. The first step in the breakdown of TRL is hy-
drolysis by the lipoprotein lipase bound to the en-
dothelial cells. The excessive amount of postprandial
chylomicroms and remnants compete with an in-
creased number of VLDL1 particles for the lipoprotein
lipase and that slows down the process of delipida-
tion35. VLDL1 production is increased in insulin resist-
ance in type 2 diabetes36. The intravascular pool of
VLDL is furthermore enhanced by the reduction of
lipoprotein lipase activity due to relative insulin deficit
and insulin resistance37. Mutations of the lipoprotein li-
pase gene38, which are common among people with the
Metabolic Syndrome, may aggravate disturbances in
TRL removal. It is an open question whether lipopro-
tein gene mutations as well as anomalies in ligand
apoproteins of hepatic remnant receptors may play an
independent role in the pathogenesis of the Metabolic
Syndrome by aggravating insulin resistance at target
organs level.
Decreases in apoprotein A1 and increases in apoB are
prominent changes in the apoprotein profile in diseases
of the Metabolic Syndrome.
Each VLDL and LDL particle contains one ApoB mol-
ecule. Increases in ApoB concentration were observed in
type 2 diabetes with coronary heart disease 38,39 .
Hypertriglyceridemic hyper ApoB was described as
atherogenic dyslipoproteinemia in type 2 diabetes
by Sniderman et al. 39 . In the Insulin Resistance
Atherosclerosis Study (IRAS)40 10% of the participants
had normal LDL-cholesterol according to NCEP criteria
but elevated ApoB. Hyper apoB subjects had a higher
percentage of abdominal obesity, other dyslipidemias
and hyperinsulinemia than subjects with increased
LDL-cholesterol, but normal ApoB. ApoB was signifi-
cantly correlated with triglyceride levels and inversely
Dyslipidemia in the Metabolic Syndrome • 353
Table 21-5. Dyslipidemia profile in Metabolic
Syndrome
Free fatty acids ↑
Triglycerides ↑↑
Postprandial chylomicrons ↑↑
Very low density lipoproteins (VLDL) ↑↑
VLDL1 ↑↑↑
VLDL2 ↑
Intermediate density lipoproteins (IDL) ↑↑
Small dense LDL ↑
High density lipoproteins (HDL) ↓↓
HDL1 ↓
HDL2 ↓↓↓
ApoB ↑
ApoA1 ↓
correlated to LDL particle size. These results support the
assumption that apoB is linked to dyslipidemia in the
Metabolic Syndrome while LDL-cholesterol is not. It is
not yet understood whether apoB measurement may re-
place or add additional value to small dense LDL deter-
mination in the diagnostic of dyslipidemia in the Meta-
bolic Syndrome.
ApoA1 plays a key role in cholesterol reverse trans-
port. ApoA 1 and ApoA 2 are the major structural
apoproteins of HDL, which can be separated by their
content of both apoproteins in subclasses that differ in
function and antiatherogenic potency41. In a cross-sec-
tional study42 with type 2 diabetes patients ApoA1 and
ApoA2 were reduced in those with coronary heart dis-
ease. As shown by Pietzsch et al.30, the apoA1 content of
HDL is already reduced in subjects with IGT. The activ-
ity of the cholesterol ester transfer protein was inverse-
ly correlated to HDL removal in this stable isotope
study and subjects with type 2 diabetes showed a defi-
ciency of apoA1-mediated reverse cholesterol trans-
port43.
So far most of our knowledge on the complex patho-
physiology of fatty acid and lipoprotein metabolism and
the Metabolic Syndrome is based on our understanding
of diabetic dyslipidemia. Visceral adiposity as a major
source of FFA for hepatic lipogenesis is another major
player (Fig. 21-3) in the pathophysiology of the Metabol-
ic Syndrome and dyslipidemia. Only little is known
about the chain of events that constitutes the interaction
between a broad spectrum of susceptibility genes that
reach far beyond lipoprotein lipase gene mutations.
Furthermore dyslipidemia in the Metabolic Syndrome is
greatly affected by over- and malnutrition and physical
activity. A diet rich in saturated fat will escalate the de-
rangement in postprandial triglyceride excursion,
whereas physical activity of the endurance type will im-
prove lipid clearance.
354 • Related Diseases in the Metabolic Syndrome
Dyslipidemia and insulin resistance
in the Metabolic Syndrome
In 1988 G. Reaven44 introduced insulin resistance as the
unifying pathophysiology of a cluster of diseases that
had been previously described as plurimetabolic syn-
drome45 and Metabolic Syndrome1. It is of interest that a
primary role for dyslipidemia, fatty acid-glucose cycle
and non-alcoholic fatty liver in the pathogenesis of the
Metabolic Syndrome had been already described in the
early description of the plurimetabolic syndrome by
G. Crepaldi45 and in the first comprehensive elaboration
of a definition and the pathophysiology by M. Hanefeld
and W. Leonhardt1. The introduction of the CLAMP tech-
nique46 and of the homeostasis model assessment of in-
sulin resistance (HOMAIR)47 revealed that insulin resist-
ance is a common finding in diseases of the Metabolic
Syndrome and closely related to all components of dys-
lipidemia. Thus, the term “insulin resistance syndrome”
had been widely used to indicate insulin resistance as
common soil48,49. In the Strong Heart Study in nondia-
betic American Indians the levels of HDL-cholesterol de-
creased and triglyceride levels increased across tertiles of
HOMAIR50. Triglycerides were increased and HDL-cho-
lesterol lowered in people with high fasting insulin com-
pared to participants with low insulin level in the San
Antonio Heart Study51. Consistent data from cross-sec-
tional52,53 and a few prospective studies13,58,59 confirm the
close relationship between dyslipidemia and insulin re-
sistance. Insulin resistance however was not related to to-
tal and LDL-cholesterol57. Nevertheless hyperinsuline-
mia and insulin resistance are inversely correlated to
LDL particle size58,59 in type 2 diabetes. This also applies
to non-diabetic subjects with insulin resistance. Insulin
resistance is associated with a preponderance of small
dense LDL in diabetic and non-diabetic subjects.
Furthermore, insulin resistance is associated with an
increase in ApoB and a decrease in apoA160. The IRIS II
study was performed in 4265 patients with type 2 dia-
betes in order to find a practical clinical algorithm for es-
timation of insulin resistance. Multiple regression analy-
sis revealed triglycerides and HDLl-cholesterol along
with fasting blood glucose and BMI as the most power-
ful predictors of insulin resistance61. The cross-sectional
design of the study does not allow us to infer whether
dyslipidemia is a consequence, a bystander or con-
tributes to insulin resistance. In prospective studies in-
creased fasting insulin or HOMAIR predicted develop-
ment of hypertriglyceridemia/low HDL as well as an in-
crease in ApoB and a decrease in ApoA162-64. In a study
by Feingold et al. 65 analyzing LDL subclasses and
triglyceride metabolism in normolipidemic subjects
compared to diabetic controls, type 2 diabetes was an in-
dependent predictor of LDL phenotype B and of slowed
clearance of triglyceride rich lipoproteins, which was
linked to insulin resistance.
Insulin resistance is also a determinant of postprandi-
al hypertriglyceridemia, regardless of the stage of glu-
cose tolerance25. At the moment there is only very limit-
ed data available from studies with drugs that specifi-
cally act on dyslipidemia, with prevention of insulin
resistance syndrome as a secondary objective.
Fibrates can reduce triglycerides by 30-50% and, at the
same time, alter the quality of lipoprotein particles. They
lower small dense LDL levels and moderately decrease
FFA levels. This is particularly useful in patients with dys-
lipidemia and the Metabolic Syndrome65. So far there is
little information on their effect in prediabetic subjects to
reduce the progression to diabetes. In the Bezafibrate
Coronary Atherosclerosis Intervention Trial (BECAIT) in
young male survivors of myocardial infarction a reduc-
tion in newly diagnosed diabetes as well as a significant
decrease in clinical coronary events were observed66.
Recently the DAIS investigators reported a reduction in
albuminuria in a prospective study with fenofibrate67.
Primary prevention trials are needed to evaluate the po-
tential role of fibrates as drugs for the treatment of the
Metabolic Syndrome. Thiazolidindiones (TZD) are a fam-
ily of PPARγ agonists which act primarily on insulin re-
sistance68. PPARγ is highly expressed in adipose tissue,
particularly of visceral fat cells, where it plays a crucial
role in the regulation of fatty acid metabolism and glu-
cose homeostasis. TZDs lower FFA and triglycerides and
increase HDL-cholesterol69,70. This is associated with a
substantial improvement in the insulin sensitivity of
muscle, liver and endothelial cells. Further pleiotropic ef-
fects in the Metabolic Syndrome are the reduction of
blood pressure in hypertensive patients71, the down-reg-
ulation of low grade inflammation72 – a new component
of Metabolic Syndrome – and the improvement in en-
dothelial function73 irrespective of the level of glycemic
control. TZD have also been effective in preventing dia-
betes in gestational women.
Thus, the actions of TZD support the hypothesis that
anomalies in adipocyte metabolism with increased FFA
may play a primary role in promoting insulin resistance
and dyslipidemia.
Dyslipidemia and vascular disease
in the Metabolic Syndrome
Elevation of FFA and other components of the lipid tri-
ad are associated with endothelial dysfunction and inti-
ma media thickening of the common carotid arteries and

Aa. femoralis75-77. In the CATHAY study78, in apparently
healthy Chinese subjects the Metabolic Syndrome was
associated with impaired flow-mediated vasodilatation.
In addition to the well- known effect of “high normal”
glucose the coexistence of dyslipidemia was also related
to endothelial dysfunction in multiple regression analy-
sis. In a comparative CLAMP study of patients with
type 2 diabetes73 the reduction of FFA by rosiglitazone
was associated with improved endothelial function,
whereas nateglinide with the same level of glucose con-
trol neither affected dyslipidemia nor endothelium-de-
pendent, flow-mediated vasodilatation or nitric oxide
release.
In the RIAD study79 dyslipidemia was associated
with an additional increase of intima-media thickness
within the frame of the Metabolic Syndrome. In multi-
variate analysis with intima media thickness as the de-
pendent variable, HDL-cholesterol was a highly signifi-
cant determinant of IMT. In univariate analysis both
triglycerides and HDL-cholesterol were significantly
correlated to intima media thickness mean. The HDL-
cholesterol/triglycerides ratio showed the best predic-
tive power80.
In a population based study77 in Swedish men aged
58 years LDL particle size was significantly lower in pa-
tients with the Metabolic Syndrome as defined by the
WHO definition. This was associated with a higher inti-
ma media thickness and plaque occurrence in the com-
mon carotid and femoral arteries. There was a signifi-
cant but weak inverse relationship between LDL-parti-
cle size and intima media thickening. In the Baltimore
longitudinal study on aging75 the presence of the Meta-
bolic Syndrome by NCEPIII criteria was associated with
higher intima media thickness and arterial stiffness. In
multiple regression analysis, taking into account each
individual component of the Metabolic Syndrome, the
clustering of traits in Metabolic Syndrome remained an
independent risk factor for intima media thickness. This
suggests that the traits act synergistically on endothelial
function and on intima media thickness, which is an es-
tablished surrogate parameter of systemic atherosclero-
sis. This hypothesis is supported by a few prospective
studies with major cardiovascular events as hard end-
points. A prospective analysis of the insulin resistance
syndrome in the San Antonio Heart Study51 has shown
that hyperinsulinemia at baseline was associated with
the subsequent development of multiple traits of the
Metabolic Syndrome in particular of high triglycerides
and low HDL-cholesterol. Patients with dyslipidemia
and the Metabolic Syndrome also had a higher risk for
the development of cardiovascular disease. In the
Bothnia study in a high risk Scandinavian population13
Dyslipidemia in the Metabolic Syndrome • 355
the risk for coronary heart disease and stroke was in-
creased threefold in patients with the Metabolic Syn-
drome applying the WHO definition. Dyslipidemia as
an individual trait had the highest relative risk for coro-
nary heart disease (RR = 1.73) and myocardial infarction
(RR = 1.71), whereas microalbuninuria was the strongest
individual predictor of cardiovascular mortality (RR =
2.80). Insulin resistance was another independent risk
factor for coronary heart disease (RR for myocardial in-
farction 2.02) but not for mortality. There was a stepwise
increase in major cardiovascular events in patients with
the Metabolic Syndrome from normal glucose tolerance
to prediabetes and to type 2 diabetes.
The Verona Diabetes Complication study 55 con-
firmed insulin resistance as measured by HOMAIR as an
independent risk factor together with HDL/total choles-
terol ratio for cardiovascular disease. The odds ratio for
total/HDL-cholesterol was 1.22. Thus among the other
traits of the Metabolic Syndrome dyslipidemia along with
insulin resistance were the only independent risk factors
for cardiovascular disease. In a population-based study81
with middle-aged Finnish men free of clinical cardiovas-
cular disease at baseline, the Metabolic Syndrome by
NCEPIII and by WHO criteria was associated with a high-
ly significant cardiovascular mortality: OR 2.9 and 2.9
resp. After adjustment for conventional risk factors the
WHO definition predicted more consistently cardiovas-
cular and all cause mortality. This study provides no data
on the contribution of the individual traits of the Meta-
bolic Syndrome to the risk of cardiovascular diseases. The
impact of the Metabolic Syndrome by NCEPIII criteria on
coronary risk was analyzed in a population with low cho-
lesterol levels in Turkey82. In this population with low
HDL and low LDL the Metabolic Syndrome was an inde-
pendent predictor of subsequent coronary heart disease
(RR 1.71). In men but not in women dyslipidemia as a sin-
gle trait was a risk factor for CHD.
Finally, in the VAHIT- a secondary intervention trial
of coronary heart disease in men with low HDL-hyper-
triglyceridemia- the effect of genfibrozil was strongly
dependent on the status of insulin sensitivity. Patients
with insulin resistance benefited more from gemfibrozil,
a drug specifically acting on triglycerides and HDL-cho-
lesterol, than those without insulin resistance83. The au-
thors conclude that, independently of triglycerides and
HDL-cholesterol values at baseline or as a result of ther-
apy, insulin resistance is associated with a higher inci-
dence of major cardiovascular events.
In conclusion, dyslipidemia may amplify the risk as
an individual component of the Metabolic Syndrome for
both diabetes and atherosclerotic vascular disease.
However it remains open to discussion to what extent
356 • Related Diseases in the Metabolic Syndrome
the risk of cardiovascular disease in the Metabolic Syn-
drome is determined by dyslipidemia as a single trait.
Studies with lipid-lowering drugs such as fibrates and
statins have given the first indication that the primary
prevention of diseases of the Metabolic Syndrome by
correcting dyslipidemia may be possible. This should be
addressed in future prospective studies.
References
1. Hanefeld M, Leonhardt W. Das metabolische Syndrom.
Dt Gesundh Wesen 1981;36:545-551.
2. Alberti KG, Zimmet PZ. Definition, diagnosis and classi-
fication of diabetes mellitus and its complications. Part 1:
diagnosis and classification of diabetes mellitus provi-
sional report of a WHO consultation. Diabet Med 1998
Jul;15(7):539-53.
3. Expert Panel on Detection, Evaluation and Treatment of
High Blood Cholesterol in Adults. Executive summary of
the third report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation
and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III), JAMA 2001;285:2486-97.
4. Reaven GM. Multiple CHD risk factors in type 2 diabetes:
beyond hyperglycemia. Diabetes Obes Metab Suppl
2002;1:13-8.
5. Haffner SM, Mykkänen L, Festa A, Burke JP, Stern MP.
Insulin-Resistant Prediabetic Subjects Have More
Atherogenic Risk Factors Than Insulin-Sensitive
Prediabetic Subjects. Implications for Preventing
Coronary Heart Disease During the Prediabetic State.
Circulation 2000;101:975-80.
6. Bonora E, Kiechl S, Oberhollenzer F, Egger G, Bonadonna
RC, Muggeo M, Willeit J. Impaired glucose tolerance,
Type II diabetes mellitus and carotid atherosclerosis:
prospective results from the Bruneck Study. Diabetologia
2000 Feb;43(2):156-64.
7. Bays H. Atherogenic dyslipidemia in type 2 diabetes and
metabolic syndrome: current and future treatment op-
tions. Br J Diabetes Vasc Dis 2003;3(5):356-360.
8. Ford ES, Giles WH, Dietz WH. Prevalence of the meta-
bolic syndrome among US adults: findings from the Third
National Health and Nutrition Examination Survey.
JAMA 2002 Jan;16:287(3):356-9.
9. Assmann G, Schulte H, Cullen P. Metabolic syndrome
and dyslipoproteinemia. In: Hanefeld M, Leonhardt W
(eds.). The Metabolic Syndrome. Gustav Fischer Jena
1997;38-49.
10. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK,
Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic
syndrome and total and cardiovascular disease mortality
in middle-aged men. JAMA 2002 Dec 4;288(21):2709-16.
11. Chen CH, Lin KC, Tsai ST, Chou P. Different association
of hypertension and insulin-related metabolic syndrome
between men and women in 8437 nondiabetic Chinese.
Am J Hypertens 2000 Jul;13(7):846-53.
12. Balkau B, Charles MA, Drivsholm T, Borch-Johnsen K,
Wareham N, Yudkin JS, Morris R, Zavaroni I, van Dam R,
Feskins E, Gabriel R, Diet M, Nilsson P, Hedblad B.
European Group For The Study Of Insulin Resistance
(EGIR). Frequency of the WHO metabolic syndrome in
European cohorts, and an alternative definition of an in-
sulin resistance syndrome. Diabetes Metab 2002
Nov;28(5):364-76.
13. Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen
M, Taskinen MR, Groop L. Cardiovascular morbidity and
mortality associated with the metabolic syndrome.
Diabetes Care 2001 Apr;24(4):683-9.
14. Kohler C, Temelkova-Kurktschiev T, Schaper F, Fucker K,
Hanefeld M. [Prevalence of newly diagnosed type 2 dia-
betes, impaired glucose tolerance and abnormal fasting
glucose in a high risk population. Data from the RIAD
study using new diagnostic criteria for diabetes]. Dtsch
Med Wochenschr 1999 Sep 17;124(37):1057-61.
15. Haffner S, Cassells HB. Metabolic syndrome - a new risk
factor of coronary heart disease? Diabetes Obes Metab
2003 Nov;5(6):359-70.
16. Alexander CM, Landsman PB, Teutsch SM, Haffner SM.
Third National Health and Nutrition Examination Survey
(NHANES III); National Cholesterol Education Program
(NCEP). NCEP-defined metabolic syndrome, diabetes,
and prevalence of coronary heart disease among
NHANES III participants age 50 years and older. NCEP-
defined metabolic syndrome, diabetes, and prevalence of
coronary heart disease among NHANES III participants
age 50 years and older. Diabetes 2003 May;52(5):1210-4.
17. Randle PJ, Garland PB, Newsholme EA, Hales CN. The
glucose fatty acid cycle in obesity and maturity onset di-
abetes mellitus. Ann N Y Acad Sci 1965 Oct 8;131(1):324-33.
18. Reaven GM, Hollenbeck C, Jeng CY, Wu MS, Chen YD.
Measurement of plasma glucose, free fatty acid, lactate,
and insulin for 24 h in patients with NIDDM. Diabetes
1988 Aug;37(8):1020-4.
19. Boden G, Jadali F. Effects of lipid on basal carbohydrate
metabolism in normal men. Diabetes 1991 Jun;40(6):686-
92.
20. Zhou YP, Grill VE. Long-term exposure of rat pancreatic
islets to fatty acids inhibits glucose-induced insulin secre-
tion and biosynthesis through a glucose fatty acid cycle. J
Clin Invest 1994 Feb;93(2):870-6.
21. McGarry JD. What if Minkowski had been ageusic? An al-
ternative angle on diabetes. Science 1992 Oct 30;
258(5083):766-70.
22. Mero N, Syvanne M, Taskinen MR. Postprandial lipid
metabolism in diabetes. Atherosclerosis 1998 Dec;141
(Suppl 1):S53-5.
23. Chen YD, Swami S, Skowronski R, Coulston A, Reaven
GM.Differences in postprandial lipemia between patients
with normal glucose tolerance and noninsulin-dependent
diabetes mellitus. J Clin Endocrinol Metab 1993 Jan;
76(1):172-7.
24. Jeppesen J, Hollenbeck CB, Zhou MY, Coulston AM,
Jones C, Chen YD, Reaven GM. Relation between insulin
resistance, hyperinsulinemia, postheparin plasma
lipoprotein lipase activity, and postprandial lipemia.
Arterioscler Thromb Vasc Biol 1995 Mar;15(3):320-4.
25. Henkel E, Temelkova-Kurktschiev T, Koehler C, Pietzsch
J, Leonhardt W, Hanefeld M. Impaired glucose tolerance
is not associated with lipid intolerance. Diabetes Nutr
Metab 2002 Apr;15(2):84-90.
26. Taskinen MR. Diabetic dyslipidemia: from basic research
to clinical practice. Diabetologia 2003 Jun;46(6):733-49.
Epub 2003 May 28.
27. Temelkova-Kurktschiev T, Hanefeld M, Leonhardt W.
Small dense low-density lipoprotein (LDL) in non-in-
sulin-dependent diabetes mellitus (NIDDM). Impact of

hypertriglyceridemia. Annals New York Academy of
Sciences 1997;827:279-86.
28. Frenais R, Ouguerram K, Maugeais C, Mahot P, Maugere
P, Krempf M, Magot T. High density lipoprotein
apolipoprotein AI kinetics in NIDDM: a stable isotope
study. Diabetologia 1997 May;40(5):578-83.
29. Lamarche B, Uffelman KD, Carpentier A, Cohn JS, Steiner
G, Barrett PH, Lewis GF. Triglyceride enrichment of HDL
enhances in vivo metabolic clearance of HDL apo A-I in
healthy men. J Clin Invest 1999 Apr;103(8):1191-9.
30. Pietzsch J, Julius U, Nitzsche S, Hanefeld M. In vivo evi-
dence for increased apolipoprotein A-I catabolism in sub-
jects with impaired glucose tolerance. Diabetes 1998
Dec;47(12):1928-34.
31. Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck
U, Schmechel H, Ziegelasch HJ, Lindner J, the DIS Group:
Risk factors for myocardial infarction and death in newly
detected NIDDM: The Diabetes Intervention Study, 11
years follow-up. Diabetologia 1996;39:1577-83.
32. DECODE Study Group, the European Diabetes
Epidemiology Group. Glucose tolerance and cardiovas-
cular mortality: comparison of fasting and 2-hour diag-
nostic criteria. Arch Intern Med 2001 Feb 12;161(3):397-
405.
33. Ceriello A, Hanefeld M, Leiter L, Monnier L, Moses A,
Owens D, Tajima N, Tuomilehto J. Postprandial glucose
regulation and diabetic complications. Arch Intern Med
2004 Oct 25;164(19):2090-5.
34. Ginsberg HN, Illingworth DR. Postprandial dyslipi-
demia: an atherogenic disorder common in patients
with diabetes mellitus. Am J Cardiol 2001 Sep 20;88
(6A):9H-15H.
35. Heine RJ, Dekker JM. Beyond postprandial hyper-
glycemia: metabolic factors associated with cardiovascu-
lar disease. Diabetologia 2002 Apr;45(4):461-75.
36. K a r p e F, O l i v e c ro n a T, H a m s t e n A , H u l t i n M .
Chylomicron/chylomicron remnant turnover in humans:
evidence for margination of chylomicrons and poor con-
version of larger to smaller chylomicron remnants. J Lipid
Res 1997 May;38(5):949-61.
37. Panarotto D, Remillard P, Bouffard L, Maheux P. Insulin
resistance affects the regulation of lipoprotein lipase in
the postprandial period and in an adipose tissue-specific
manner. Eur J Clin Invest. 2002 Feb;32(2):84-92.
38. Mero N, Suurinkeroinen L, Syvanne M, Knudsen P, Yki-
Jarvinen H, Taskinen MR. Delayed clearance of postpran-
dial large TG-rich particles in normolipidemic carriers of
LPL Asn291Ser gene variant. J Lipid Res 1999
Sep;40(9):1663-70.
39. S n i d e r m a n A D , S c a n t l e b u r y T, C i a n f l o n e K .
Hypertriglyceridemic hyperapob: the unappreciated
atherogenic dyslipoproteinemia in type 2 diabetes melli-
tus. Ann Intern Med 2001 Sep 18;135(6):447-59.
40. Williams K, Sniderman AD, Sattar N, D’Agostino R Jr,
Wagenknecht LE, Haffner SM. Comparison of the associ-
ations of apolipoprotein B and low-density lipoprotein
cholesterol with other cardiovascular risk factors in the
Insulin Resistance Atherosclerosis Study (IRAS).
Circulation 2003 Nov 11;108(19):2312-6.
41. Pascot A, Lemieux I, Prud’homme D, Tremblay A,
Nadeau A, Couillard C, Bergeron J, Lamarche B, Despres
JP. Reduced HDL particle size as an additional feature of
the atherogenic dyslipidemia of abdominal obesity. J
Lipid Res 2001 Dec;42(12):2007-14.
Dyslipidemia in the Metabolic Syndrome • 357
42. Syvanne M, Kahri J, Virtanen KS, Taskinen MR. HDLs
containing apolipoproteins A-I and A-II (LpA-I:A-II) as
markers of coronary artery disease in men with non-in-
sulin-dependent diabetes mellitus. Circulation 1995 Aug
1;92(3):364-70.
43. Syvanne M, Castro G, Dengremont C, De Geitere C,
Jauhiainen M, Ehnholm C, Michelagnoli S, Franceschini
G, Kahri J, Taskinen MR. Cholesterol efflux from Fu5AH
hepatoma cells induced by plasma of subjects with or
without coronary artery disease and non-insulin-depend-
ent diabetes: importance of LpA-I:A-II particles and
phospholipid transfer protein. Atherosclerosis 1996 Dec
20;127(2):245-53.
44. Reaven GM. Banting lecture 1988. Role of insulin resistance
in human disease. Diabetes 1988 Dec;37(12):1595-607.
45. Crepaldi G, Manzato E. [Polymetabolic syndrome].
Minerva Endocrinol 1995 Sep;20(3):155-60.
46. DeFronzo RA, Tobin JD, Andrés R. Glucose clamp tech-
nique: a method for quantifying insulin secretion and re-
sistance. Am J Physiol 1979 Sep;237(3):E214-23.
47. Matthews DR, Hosker JP, Rudenski AS, Naylor BA,
Treacher DF, Turner RC. Homeostasis model assessment:
insulin resistance and beta-cell function from fasting plas-
ma glucose and insulin concentrations in man.
Diabetologia 1985 Jul;28(7):412-9.
48. Stern MP. Diabetes and cardiovascular disease. The “com-
mon soil” hypothesis. Diabetes 1995 Apr;44(4):369-74.
49. DeFronzo RA, Ferrannini E. Insulin resistance. A multi-
faceted syndrome responsible for NIDDM, obesity, hy-
pertension, dyslipidemia, and atherosclerotic cardiovas-
cular disease. Diabetes Care 1991 Mar;14(3):173-94.
50. Resnick HE, Jones K, Ruotolo G, Jain AK, Henderson J, Lu
W, Howard BV. Strong Heart Study. Insulin resistance, the
metabolic syndrome, and risk of incident cardiovascular
disease in nondiabetic American indians: the Strong
Heart Study. Diabetes Care 2003 Mar;26(3):861-7.
51. Haffner SM, Valdez RA, Hazuda HP, Mitchell BD,
Morales PA, Stern MP. Prospective analysis of the insulin-
resistance syndrome (syndrome X). Diabetes 1992
Jun;41(6):715-22.
52. Orchard TJ, Becker DJ, Bates M, Kuller LH, Drash AL.
Plasma insulin and lipoprotein concentrations: an athero-
genic association? Am J Epidemiol 1983 Sep;118(3):326-37.
53. Laakso M, Pyorala K, Voutilainen E, Marniemi J. Plasma
insulin and serum lipids and lipoproteins in middle-aged
non-insulin-dependent diabetic and non-diabetic sub-
jects. Am J Epidemiol 1987 Apr;125(4):611-21.
54. Hanley AJ, Festa A, D’Agostino RB Jr, Wagenknecht LE,
Savage PJ, Tracy RP, Saad MF, Haffner SM. Metabolic and
inflammation variable clusters and prediction of type 2
diabetes: factor analysis using directly measured insulin
sensitivity. Diabetes 2004 Jul;53(7):1773-81.
55. Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini
F, Zenari L, Saggiani F, Poli M, Perbellini S, Raffaelli A,
Cacciatori V, Santi L, Targher G, Bonadonna R, Muggeo M.
HOMA-estimated insulin resistance is an independent pre-
dictor of cardiovascular disease in type 2 diabetic subjects:
prospective data from the Verona Diabetes Complications
Study. Diabetes Care 2002 Jul;25(7):1135-41.
56. Hu G, Qiao Q, Tuomilehto J, Balkau B, Borch-Johnsen K,
Pyorala K. DECODE Study Group. Prevalence of the
metabolic syndrome and its relation to all-cause and car-
diovascular mortality in nondiabetic European men and
women. Arch Intern Med 2004 May 24;164(10):1066-76.
358 • Related Diseases in the Metabolic Syndrome
57. Karhapaa P, Voutilainen E, Kovanen PT, Laakso M.
Insulin resistance in familial and nonfamilial hypercho-
lesterolemia. Arterioscler Thromb 1993 Jan;13(1):41-7.
58. Barakat HA, Carpenter JW, McLendon VD, Khazanie P,
Leggett N, Heath J, Marks R. Influence of obesity, im-
paired glucose tolerance, and NIDDM on LDL structure
and composition. Possible link between hyperinsulinemia
and atherosclerosis. Diabetes 1990 Dec;39(12):1527-33.
59. Reaven GM, Chen YD, Jeppesen J, Maheux P, Krauss RM.
Insulin resistance and hyperinsulinemia in individuals
with small, dense low density lipoprotein particles.
J Clin Invest 1993 Jul;92(1):141-6.
60. Mykkanen L, Kuusisto J, Haffner SM, Pyorala K, Laakso
M. Hyperinsulinemia predicts multiple atherogenic
changes in lipoproteins in elderly subjects. Arterioscler
Thromb 1994 Apr;14(4):518-26.
61. Forst T, Standl E, Hohberg C, Konrad T, Schulze J,
Strotmann HJ, Lubben G, Pahler S, Bachinger A,
Langenfeld M, Pfutzner A. IRIS II study: the IRIS II
score—assessment of a new clinical algorithm for the
classification of insulin resistance in patients with Type 2
diabetes. Diabet Med 2004 Oct;21(10):1149-53.
62. Tomkin GH, Owens D. Abnormalities in apo B-containing
lipoproteins in diabetes and atherosclerosis. Diabetes
Metab Res Rev 2001 Jan-Feb;17(1):27-43.
63. Ronnemaa T, Laakso M, Kallio V, Pyorala K, Marniemi J,
Puukka P. Serum lipids, lipoproteins, and apolipopro-
teins and the excessive occurrence of coronary heart dis-
ease in non-insulin-dependent diabetic patients. Am J
Epidemiol 1989 Oct;130(4):632-45.
64. Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss
RM. LDL subclass phenotypes and triglyceride metabo-
lism in non-insulin-dependent diabetes. Arterioscler
Thromb 1992 Dec;12(12):1496-502.
65. Steiner G. Fibrates in the metabolic syndrome and in dia-
betes. Endocrinol Metab Clin North Am 2004 Sep;
33(3):545-555.
66. Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de
Faire U. Angiographic assessment of effects of bezafibrate
on progression of coronary artery disease in young male
postinfarction patients. Lancet 1996 Mar 30;347(9005):849-
53.
67. [No authors listed]. Effect of fenofibrate on progression of
coronary-artery disease in type 2 diabetes: the Diabetes
Atherosclerosis Intervention Study, a randomised study.
Lancet 2001 Mar 24;357(9260):905-10. Erratum in: Lancet
2001 Jun 9;357(9271):1890.
68. Carey DG, Cowin GJ, Galloway GJ, Jones NP, Richards
JC, Biswas N, Doddrell DM. Effect of rosiglitazone on in-
sulin sensitivity and body composition in type 2 diabetic
patients Obes Res 2002 Oct;10(10):1008-15. Erratum in:
Obes Res 2002 Nov;10(11):following table of contents.
69. Campbell IW. Antidiabetic drugs present and future:
will improving insulin resistance benefit cardiovascular
risk in type 2 diabetes mellitus? Drugs 2000 Nov;
60(5):1017-28.
70. Raji A, Seely EW, Bekins SA, Williams GH, Simonson DC.
Rosiglitazone improves insulin sensitivity and lowers
blood pressure in hypertensive patients. Diabetes Care
2003 Jan;26(1):172-8.
71. Grossman E. Rosiglitazone reduces blood pressure and
urinary albumin excretion in type 2 diabetes: G Bakris et
al. J Hum Hypertens 2003 Jan;17(1):5-6.
72. Haffner SM, Greenberg AS, Weston WM, Chen H,
Williams K, Freed MI. Effect of rosiglitazone treatment on
nontraditional markers of cardiovascular disease in pa-
tients with type 2 diabetes mellitus. Circulation 2002 Aug
6;106(6):679-84.
73. Pistrosch F, Passauer J, Fischer S, Fuecker K, Hanefeld M,
Gross P. In type 2 diabetes, rosiglitazone therapy for in-
sulin resistance ameliorates endothelial dysfunction inde-
pendent of glucose control. Diabetes Care 2004 Feb;
27(2):484-90.
74. Snitker S, Watanabe RM, Ani I, Xiang AH, Marroquin A,
Ochoa C, Goico J, Shuldiner AR, Buchanan TA.
Troglitazone in Prevention of Diabetes (TRIPOD) study.
Changes in insulin sensitivity in response to troglitazone
do not differ between subjects with and without the com-
mon, functional Pro12Ala peroxisome proliferator-acti-
vated receptor-gamma2 gene variant: results from the
Troglitazone in Prevention of Diabetes (TRIPOD) study.
Diabetes Care 2004 Jun;27(6):1365-8.
75. Scuteri A, Najjar SS, Muller DC, Andres R, Hougaku H,
Metter EJ, Lakatta EG. Metabolic syndrome amplifies the
age-associated increases in vascular thickness and stiff-
ness. J Am Coll Cardiol 2004 Apr 21;43(8):1388-95.
76. McNeill AM, Rosamond WD, Girman CJ, Heiss G,
Golden SH, Duncan BB, East HE, Ballantyne C.
Prevalence of coronary heart disease and carotid arterial
thickening in patients with the metabolic syndrome (The
ARIC Study). Am J Cardiol 2004 Nov 15;94(10):1249-54.
77. Hulthe J, Bokemark L, Wikstrand J, Fagerberg B. The meta-
bolic syndrome, LDL particle size, and atherosclerosis: the
Atherosclerosis and Insulin Resistance (AIR) study.
Arterioscler Thromb Vasc Biol 2000 Sep;20(9):2140-7.
78. Thomas GN, Chook P, Qiao M, Huang XS, Leong HC,
Celermajer DS, Woo KS. Deleterious impact of “high nor-
mal” glucose levels and other metabolic syndrome com-
ponents on arterial endothelial function and intima-me-
dia thickness in apparently healthy Chinese subjects: the
CATHAY study. Arterioscler Thromb Vasc Biol 2004
Apr;24(4):739-43. Epub 2004 Jan 22.
79. Temelkova-Kurktschiev TS, Koehler C, Leonhardt W,
Schaper F, Henkel E, Siegert G, Hanefeld M. Increased in-
timal-medial thickness in newly detected type 2 diabetes:
risk factors. Diabetes Care 1999 Feb;22(2):333-8.
80. Temelkova-Kurktschiev T, Hanefeld M. The lipid triad in
type 2 diabetes - prevalence and relevance of hyper-
triglyceridemia/low high-density lipoprotein syndrome
in type 2 diabetes. Exp Clin Endocrinol Diabetes 2004
Feb;112(2):75-9.
81. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK,
Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic
syndrome and total and cardiovascular disease mortality
in middle-aged men. JAMA 2002 Dec 4;288(21):2709-16.
82. Onat A, Ceyhan K, Basar O, Erer B, Toprak S, Sansoy V.
Metabolic syndrome: major impact on coronary risk in a
population with low cholesterol levels—a prospective
and cross-sectional evaluation. Atherosclerosis 2002
Dec;165(2):285-92.
83. Robins SJ, Rubins HB, Faas FH, Schaefer EJ, Elam MB,
Anderson JW, Collins D. Veterans Affairs HDL
Intervention Trial (VA-HIT). Insulin resistance and car-
diovascular events with low HDL cholesterol: the
Veterans Affairs HDL Intervention Trial (VA-HIT).
Diabetes Care 2003 May;26(5):1513-7.