Effects of a Paleolithic diet in subjects with markers of the metabolic syndrome. A pilot-study.

The metabolic syndrome is a clustering of symptoms that reflect overnutrition,
sedentary lifestyles, and resultant excess adiposity. There are at least 5
definitions of the metabolic syndrome (Cornier et al., 2008). As a common
denominator, they all include (abdominal) obesity, insulin
resistance/compromised glucose homeostasis, dyslipidemia, and elevated blood
pressure and these are associated with diseases and conditions such as the
prothrombotic state, proinflammatory state, non-alcoholic fatty liver disease,
reproductive disorders and most prominently diabetes mellitus type 2 and
cardiovascular disease. The metabolic syndrome has become one of the major
public health concerns worldwide, not only affecting the industrialized world,
but also the developing nations which experience a rapid transition of
nutrition. The prevalence of the metabolic syndrome is increasing to epidemic
proportions, affecting up to 12-40% of subjects, depending on the definition,
sex, race, country and others (Lorenzo et al., 2007; Cameron et al., 2007;
Deepa et al, 2007; Csaszar et al, 2006). Since the prevalence of the metabolic
syndrome world wide is increasing towards epidemic proportions and individuals
with the metabolic syndrome are at high risk to progress into type 2 diabetes
mellitus (Grundy 2006; Ford et al., 2008) or cardiovascular disorders (CVD)
(Gami et al., 2007), prevention is warranted. The prevalence of MetS in the
Netherlands is about 15.5% (Donk van den et al. 2009), even in a young adult
population of the age of 36 years in the Netherlands was 18.3% in men and 3.2%
in women according to the Amsterdam Growth and Health Longitudinal Study
(Ferreira et al. 2005)From an evolutionary approach it has been postulated that
foods that were regularly eaten by hunter-gatherers during human evolution, in
particular during the Paleolithic (the old stone age, 2.5 - 0.01 million years
BP), may be optimal for prevention and treatment of metabolic disorders such as
obesity, type 2 diabetes mellitus, cardiovascular disease and insulin
resistance (Cordain et al., 2005; Eaton et. al, 1997,2000; Jansson, 1990; Mann,
2004, O*Keefe et al., 2004, Sebastian et al., 2002, 2006). A Paleolithic diet
of these days is a modern dietary regimen based on lean meat, fish, shellfish,
fruits, vegetables, roots, eggs and nuts. The Paleolithic diet contains no
grains, dairy products, added salt or refined fat and sugar (Cordain et al.
2000). Recent studies in nonobese healthy volunteers have shown that a
Paleolithic diet effectively lowers blood pressure, body weight, waist
circumference, body mass index (BMI) (Osterdahl et al. 2008), but also serum
lipids (LDL-cholesterol and triglycerides) and plasma insulin versus time Area
Under the Curve, during an Oral Glucose Tolerance Test (OGTT) (Frasetto et al.
2009). These favorable effects in healthy volunteers were observed within a
relatively short period of dietary intervention i.e. less than 2-3 weeks. The
major limitation of the studies by Osterdahl (2008) and Frasetto (2009) were
the lack of a control group. In a study by Lindeberg et al (2007) the effect of
a Paleolithic diet was compared to a Mediterranean diet in subjects with
ischaemic heart disease. A larger improvement of glucose tolerance was observed
after a Paleolithic diet. In line with these findings, a Paleolithic diet
significantly improved glycemic control compared to a conventional diabetes
diet in patients with type 2 diabetes (Jonsson et al. 2009). Although dietary
management and lifestyle modifications are considered to be the cornerstone in
the treatment and prevention of metabolic disorders, specific guidelines for
treatment of the metabolic syndrome have not yet been established . A moderate
weight loss (5-10%) has shown to be beneficial in subjects with the metabolic
syndrome (Ilanne-Parikka et al., 2008). However, more research is needed to
identify which metabolic markers/pathways can be positively influenced by
different types of diet, independent of weight loss, and which nutrient
components in a diet may improve the metabolic and




physiological status of subjects with the metabolic syndrome. Based on the
previously published favorable effects in subjects with type 2 Diabetes and
ischaemic heart disease, the present study has been proposed to investigate
whether a Paleolithic diet may be effective in subjects with the metabolic
syndrome.

We propose a 2-week randomized controlled, single-blinded pilot study to
compare the health effects of a Paleolithic diet and an isocaloric reference
diet (based on the *Guidelines for a healthy diet 2006*) on markers of the MetS
which are risk factors for the initiation and further progression into DM2 and
CVD.

The aim of the present pilot is to study whether there are changes in the
different parameters of the MetS as a result of a Palaeolithic diet compared to
an isocaloric reference diet. It has been hypothesized that a change in the
diet to one that resembles that of hunter-gatherers would be beneficial to
health. Recent studies have shown that consumption of a Paleolithic type diet,
high in lean meats, fruits, vegetables and nuts, rapidly leads to metabolic and
physiologic improvement in subjects with DM2 and ischemic heart disease.

-The main goal is to get insight which specific parameters show changes and
their effect size, to use this knowledge in the design of probable future
trials. Until now there is no research about the possible health effects of
Palaeolithic nutrition in subjects with the MetS. In former research about the
effects of a Palaeolithic diet, discussion was raised whether this positive
health effects could be caused by less energy intake or weight loss. In our
present pilot study we will try to keep energy intake and weight stable in both
intervention groups.

Working hypothesis is that a Palaeolithic diet can improve the parameters of
the MetS: glucose tolerance, fasting insulin, fasting glucose, serum total-,
LDL- and HDL-cholesterol and triglycerides, waist circumference and blood
pressure through metabolic alterations that are independent of weight loss.

-Next to this we aim to study some other outcome variables, which are assumed
to be positively influenced by the Palaeolithic diet: inflammation parameters,
intestinal permeability, HOMA and the diurnal cortisol slope in subjects with
the MetS through metabolic alterations that are independent of weight loss.
Possible alterations in these outcome parameters may give new insights in the
pathophysiological mechanisms underling the MetS and CVD.

-Another goal of the study is to obtain more information on feasibility and how
to design and develop an innovative dietary prevention program on the basis of
a Palaeolithic diet. Since specific guidelines for the treatment of the MetS
are lacking, a dietary Palaeolithic program of which the effects are
scientifically evaluated, may contribute to the prevention of the MetS and
further development into CVD and DM2

A randomized, controlled, single-blinded pilot study.

A Paleolithic diet for 14 days compared to an isocaloric diet consistent with
*Guidelines for a healthy diet 2006* of the Health Council of the Netherlands.

To our knowledge, no study has been performed up till now in which the effects
of a Paleolithic diet are investigated in subjects with the metabolic syndrome.
Innovative elements in the proposed study are reflected in the defined primary
and secondary outcome criteria. Besides the well-known risk factors as fasting
glucose, insulin, serum lipids and glucose intolerance, other outcome
parameters will be measured such as endothelial dysfunction, intestinal
permeability and fatty acid composition of erythrocytes. Possible positive
alterations in these outcome parameters may have great benefits for the
participating subjects. Since specific guidelines for the treatment of the
metabolic syndrome are lacking, a dietary Paleolithic program of which the
effects are scientifically evaluated, may contribute to the prevention of the
metabolic syndrome and further development into type 2 diabetes mellitus and
cardiovascular disease.

The study intervention is a diet intervention. There are no negative influences
known or expected from either the paleolithic diet, as from the reference diet.
According to protocol guidelines participants will access at 5 visits.
Bloodsamples will be drawn (3 times) and 24 hr-urine will be collected (2
times), subjects will have short time fasting periodes (from 20.00 oclock in
the evening) till examination/ measurements the next morning (5 times), and
non-invasive measurements will be performed (2 times). Risks for participating
subjects are expected to be low. All measurements will be performed in a 15
days period, so it will be a high intensive, but rather short ,low-risk burden
on participating subjects.