Soy Nut Study on Markers of Health

The objective of the study is to investigate the metabolomic response to consumption of soy
protein containing polyphenolic phytochemicals (isoflavones). The aim of this pilot study is
to demonstrate proof of concept and ability to detect metabolomic changes that are
responsive to soy. This preliminary data will then be used to design future research
projects.

Food phytochemicals such as the polyphenolic flavonoids from a wide variety of foods and
beverages have been associated with cardiovascular protective effects in epidemiologic
studies. Significant controversy exists in the literature regarding the efficacy and
mechanisms for the cardiovascular protection of soy foods. The soy hypothesis for
cardiovascular risk reduction has been focused mainly on the isoflavone content of soy, but
uncertainty still exists regarding the bioactive component(s). In particular, consumption of
soy protein foods has been associated with favorable cardiovascular disease (CVD) risk
profiles in population based studies. Controlled clinical trials and meta-analyses however,
have resulted in the conclusions that soy protein with associated isoflavones has only
modest hypocholesterolemic effects in the range of 3-5% reduction in LDL-cholesterol.
Additional cardioprotective effects have been demonstrated in clinical trials, promoting
small but significant changes in vascular endothelial function and antioxidant protection.
An important observation is that animal studies have shown reduction in atherosclerotic
lesion size both with and without decreased blood lipid levels. These results taken together
suggest that soy and soy phytochemicals can promote positive risk factors and outcomes by
mechanisms in addition to, and other than lowering serum cholesterol levels. There is a need
for greater understanding of the cellular and molecular mechanisms underlying the
physiologic responses to isoflavones in the vascular compartment. Increasing evidence is
emerging that biologically relevant concentrations of isoflavones may impact cell signaling
processes in vascular and other tissues.

The large body of literature on human clinical trials of soy proteins and isoflavones has
focused primarily on traditional lipid and lipoprotein parameters, biomarkers of CVD risk,
and functional changes in endothelial function, platelet activation and total blood
antioxidant capacity as described above. It is possible and likely that the effect of soy
consumption on CVD risk is a net result of multiple subtle changes in metabolic pathways,
vascular inflammatory responses and cell-signaling pathways which are not readily detected
in healthy individuals. Since individuals with metabolic syndrome (MetS) present with many
of the metabolic aberrations purported to be improved through soy food ingestion, these
individuals may be an excellent study population in order to investigate the effects of a
soy food intervention on metabolic markers of health. Equol is the end-product of daidzein
biotransformation, and is produced only by some humans, resulting in a phenotypic
characteristic in response to dietary soy. It is hypothesized by some researchers that the
"equol producers" may have additional metabolic and phenotypic responses to soy which may
help to explain some of the variances in the literature. Few investigators have examined
this question in existing studies, with two reporting an association with outcomes and one
no association. A recent study using microarray analysis of lymphocytes from postmenopausal
women demonstrated differential gene expression in women who form equol compared to those
who do not, suggesting that equol status may be an important modulator of responses to soy
isoflavones. No studies have examined this question in a metabolomic investigation. This
demonstrates a gap in the literature and provides an opportunity to contribute significant
novel data using cutting-edge approaches.

Inclusion Criteria:

- Postmenopausal women

- Men ages 45 or above

- Blood pressure greater than or equal to 130/85 mmHg but not greater than 160/100 and
meeting an additional 2 of the remaining 4 Metabolic syndrome diagnostic criteria as
defined by NCEP ATP III:

1. Elevated waist circumference: men equal to or greater than 40 inches, women
equal to or greater than 35 inches

2. Reduced HDL cholesterol: men less than 40 mg/dL, women less than 50 mg/dL

3. Fasting glucose greater than or equal to 100 mg/dL

4. Fasting blood triglycerides greater than or equal to 150 mg/dL but less than 400
mg/dL

- Weight of at least 110 pounds

Exclusion Criteria:

- Smokers

- Chronic disease, such as diabetes, cancer, renal disease, and blood disorders

- History of intestinal disorders, which affect absorption or transit, such as
ulcerative colitis or crohns disease

- Allergy to soy

- Antioxidant supplement usage