Employing dynamic kinetic responses to demonstrate the effectiveness of dietary intervention: A challenge-based study using a low-glycaemic load diet

In general nutrition research aims at optimizing health and preventing
diseases. However, the effects of dietary interventions are in general subtle,
and few relevant biomarkers are available to show that nutrition has an effect
on health or risk factors for diseases. The WHO has defined health in the year
1946 as: *a state of complete physical, mental and social well-being and not
merely the absence of disease or infirmity. More recently a new definition has
been proposed for health and wellbeing, defining health as: *the ability to
cope with daily challenges*. This adaptive capacity is also called *phenotypic
flexibility* (PF). The concept is based on the hypothesis that the dynamic
responses of key physiological processes are more indicative of health and
wellbeing states than the more common baseline measurements of biomarkers. The
principle of PF is particularly established in the area of metabolic
flexibility, which, in a strict sense, is defined as the capability to switch
between fat and glucose oxidation after a meal. The gold standard for measuring
this defined metabolic flexibility is the change in respiratory quotient (RQ)
upon a hyperinsulinemic euglycemic clamp, although RQ can also be measured upon
a mixed meal. It has been shown that metabolic flexibility plays a role in
multiple health areas such as metabolic syndrome, diabetes, cardiovascular
health, weight management, oxidative stress and inflammation. It is affected by
lifestyle such as exercise, stress, sleep, and it is known to be altered in
compromised diseased population (e.g. overweight subjects) and can be modulated
by food ingredients, diets or caloric restriction.

Primary objective: To assess the impact of a low glycaemic load (GL) diet as
compared to a *Western* diet on metabolic flexibility (the change in RQ) upon a
hyperinsulinemic euglycemic clamp.

Secondary objectives: 1) To assess the impact of low GL diet as compared to a
*Western* diet on metabolic flexibility (the change in RQ) upon a mixed meal
challenge, 2) to assess the impact of a low GL diet as compared to a *Western*
diet on the kinetic response of multiple PF markers during a mixed meal
challenge, 3) To assess the kinetic response of PF markers during a mixed meal
challenge over baseline measurements (fasted state), 4) to assess the impact of
a low GL diet as compared to a *Western* diet on these PF markers in the fasted
state, and 5) to assess the impact of a low GL diet as compared to a *Western*
diet on insulin sensitivity.

In the current study, the effectiveness of a dietary intervention will be
studied by means of measuring the change in RQ upon a hyperinsulinemic
euglycemic clamp challenge and by means of measuring the kinetic responses of
multiple PF markers (including RQ) to an acute mixed meal challenge before and
after a 6-week dietary intervention. The challenges will be applied to
investigate whether the kinetic response is a better measure for health and
wellbeing when compared to fasting (baseline) levels. In addition, several
measures that reflect perceivable benefits like mood, quality of life, sleep
quality, cognitive and physical performance will be assessed in a first
exploratory attempt to link (changes in) PF to consumer perceivable benefits.

Subjects will first be subjected to a 2-week run-in diet consisting of products
that fit into a typical *Western* diet. Thereafter subjects will be randomly
allocated to a low glycemic load diet or a *Western* diet for 6 weeks. Before
and after the intervention several measurements will take place. The low
glycemic load diet will be high in polyphenols, protein, vegetables, pulses,
fibres and nuts, and low in glycemic carbohydrates. All these dietary factors
have been shown to improve glycemic control and/or to reduce metabolic syndrome
risk factors.

Results of this study will provide insight into whether the kinetic response is
a better measure for health and wellbeing when compared to fasting levels. No
direct health benefit for the participants is expected. However, there are some
burden and risks associated with the study; large time investment (13 visits
and ca. 38 hours spent at the test facility), being committed to a specific
diet for 2+6 weeks and wearing several devices at home, which will affect
subjects daily life and finally undergoing several test at the test facility
with minor risks, such as blood sampling, which can cause a local hematoma or
bruise.