Appendix B: Additional Examples of the Effects of Functional

Appendix B: Additional Examples of the Effects of
Functional Components of Foods
A number of functional foods including soluble fiber
(Nicolosi et al., 1999), plant sterols (Thurnham, 1999),
and polyunsaturated and monounsaturated fats have
been shown to favorably influence cholesterol levels.
More recently, it appears that many chronic disease
conditions including heart disease (Ridker et al., 1997),
peripheral vascular disease (Ridker et al., 1998), diabetes
(Arnalich et al., 2000), obesity (Visser et al., 1999), and
certain cancers (Barber et al., 1999) may be chronic inflammatory conditions. Therefore a biomarker for inflammation
is needed. C-reactive protein, a protein made by the liver in
response to inflammatory or infectious stimulation (Bistrian,
1998) has been proposed. For instance, the poorer the
glycemic control in diabetes, the higher the C-reactive protein
and the poorer the outcome (Stehouwer et al., 2002). The
usual upper limit concentration of C-reactive protein in
normal subjects is 8 mg/L, and levels in poorly controlled
diabetes and obesity exceed that.
A new highly sensitive test for C-reactive protein, which
includes the usual normal range of 1-8 mg/L, has been shown
to mark coronary artery disease risk (Rader, 2000). Subjects
in the highest quartile for this highly sensitive C-reactive
protein have nearly a tripling of risk for coronary artery
disease when compared to those in the lowest quartile (Ridker
et al., 1997). Furthermore, recent studies show that half of the
benefit of statins to reduce coronary artery disease risk comes
not from the lowering of cholesterol but from the lowering of
C-reactive protein levels (Nissen et al., 2005; Ridker et al.,
2001; Ridker et al., 2005). It may be that C-reactive protein
is actually a biomarker for underlying biological changes.
Levels of C-reactive protein may be affected by infectious
diseases and other confounding conditions that would
complicate the interpretation of C-reactive protein levels
as a measure of effects of functional foods.
Soy has a history of use as food in many regions of the
world. However, although both the safety and efficacy of
soy foods in lowering circulating cholesterol has been
documented, ongoing research on other potential health
effects of soy and soy constituents suggests that we must
remain cautious in increasing these active components in
Western diets. In particular, data on cancer prevention by
soy and soy constituents is less convincing. Case-control
epidemiological studies suggest that soy foods or other
plant-based foods in the Asian diet are associated with lower
cancer rates (Birt, 2001). Some epidemiological studies
suggest that while some soy-based foods such as tofu were
associated with reduced rates of cancer in Asia, others
(such as fermented soy foods) did not seem to possess this
Expert Report
property (Birt, 2001). Prospective or intervention studies
assessing the ability of soy foods in cancer prevention have
not been conducted.
There is considerable interest in the role of isoflavones
in the prevention of breast cancer with some investigators
suggesting that early life exposure to dietary soy may be
particularly important in preventing this disease in animal
models. In contrast, animal investigations and recent
human studies suggest that isoflavones or soy foods may
actually increase the growth of breast cancers (Birt, 2001;
McMichael-Phillips et al., 1998). This was not surprising
because of the known estrogenic activity of isoflavones.
Indeed, recent reports have suggested that women with
breast cancer should avoid isoflavone-rich foods such as
soybeans (de Lemos, 2001).
Two areas of considerable interest for assessing the
value of functional foods are obesity and cancer. Obesity
has become epidemic in the United States and the world
in general. Although there are multiple causes of obesity,
including increased food intake and reduced energy expenditure, there is still considerable controversy about the role
of other factors such as the ratio of fat to carbohydrate. In
addition, there is considerable recent interest in the role that
the glycemic index (the relative insulin response to a given
amount of dietary carbohydrate intake) may play in increasing the prevalence of obesity (Ludwig, 2002; Willett et al.,
2002). Some researchers have proposed that the higher the
intake of high glycemic index foods, the greater the risk
of obesity and the so-called insulin resistance syndrome
(Ludwig, 2002; Willett et al., 2002). If valid, measuring
the glycemic index of foods and assessing insulin resistance
by simple measures such as the insulin sensitivity index
(fasting glucose/fasting insulin) could be appropriate
biomarkers for assessing the role that functional foods
may play in obesity.
An authoritative review of the available literature by
the American Diabetes Association (ADA) (Sheard et al.,
2004) concluded that at this time, there is insufficient
information to determine whether there is a relationship
between glycemic index or glycemic load of diets and the
development of diabetes. The efficacy of the glycemic index
on overall blood glucose control indicates that the use of
this technique can provide an additional benefit over that
observed when total carbohydrate is considered alone.
However, since much of the risk of developing type 2
diabetes is attributable to obesity, maintenance of a healthy
body weight is strongly recommended as a means of
preventing this disease. ADA concluded that the relationship
between glycemic index and glycemic load and the development of type 2 diabetes remains unclear at this time.
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The assessment of immune function and its relationship
to the risk of infectious disease and chronic illnesses such
as cancer has also been considered in the evaluation of
functional foods. The tests commonly employed to assess
immune function illustrate the earlier points made about
biomarkers. Isolated lymphocytes or peripheral blood
mononuclear cells can be used to assess rates of transformation or production of cytokines when stimulated by mitogens or endotoxin. The putative effect of functional foods
would be to increase this reactivity albeit within the normal
range. Similarly, another sensitive measure of immune
function is the delayed hypersensitivity skin response that
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measures the response to the intradermal injection of
common recall skin antigens like candida, trichophyton,
and mumps. In this case, an effective immune-enhancing
functional food should produce a larger response. As in
other measures, virtually all healthy subjects will have
reactivity within a “normal” range and consumption of the
functional food would shift the reactivity to a more favorable level. Of course, it is not a foregone conclusion that
increased responsiveness is necessarily beneficial under all
conditions. Under certain conditions, heightened reactivity
might increase the risk for allergic disorders (BraunFahrlander et al., 2002).
Institute of Food Technologists