Personalized Glucose Optimisation through Nutritional Intervention

A healthy lifestyle is an essential element to release the physical and mental
potential of every individual and is able to prevent the epidemic development
of overweight, and cardio- metabolic diseases. Unfortunately, most people do
not manage to incorporate or maintain the recommended changes in their daily
lifestyle. This may be due to the fact that people do not perceive the benefits
of a healthy lifestyle in the short term, nor the adverse effects of an
unhealthy lifestyle. It is increasingly recognized that maintaining
well-controlled blood glucose concentrations is essential for remaining healthy
and preventing chronic metabolic diseases. Additionally, there is evidence that
well-controlled blood glucose concentrations - by boosting physical and mental
energy - may be an important determinant of well-being, mental and physical
performance. The link between blood glucose and the latter factors has hardly
been studied. Moreover, it is not known to what extent these relationships
differ in healthy participants and participants with an impaired glucose
metabolism. When people feel better, fitter and/or otherwise motivated to
follow a dietary advice, for example, by personalized feedback on physiological
measures of glucose control or other indicators of health status, the
implementation of a healthy lifestyle is expected to be more successful.

Furthermore, despite being compliant to lifestyle advice, the metabolic
flexibility to respond to dietary intervention may vary between individuals.
Recent evidence indicates that insulin resistance and metabolic inflexibility
may develop separately in different organs, representing different etiologies
towards cardio-metabolic diseases. Interestingly, these tissue-specific
sub-phenotypes may have a differential response to diet. In a recent
ground-breaking study, it was shown that, despite high inter-individual
variability in glycemic response, responses to individual meals in daily life
could be more accurately predicted by means of an algorithm that included
lifestyle factors (diet, physical activity) and microbial composition as
compared to a prediction by common practice. The above data suggest that
successful lifestyle interventions may require a more personalized approach.
Therefore, we hypothesize that phenotype-based dietary intervention optimizes
beneficial effects on blood glucose regulation, metabolic health and
subsequently mental and physical performance and well-being.

To obtain insight into the metabolic and lifestyle determinants of postprandial
blood glucose responses and to establish the effect of macronutrient
manipulation of a 12-week dietary intervention on blood glucose homeostasis in
metabolically different groups and its relationship to physical and mental
performance and well-being.

Two-center dietary intervention study with a double-blind, randomized,
controlled parallel design. The metabolic phenotype will be blinded to the
participants and researchers.

During a period of 12 weeks, each group will receive either a diet optimal for
MIR or a diet optimal for LIR with respect to disposition index as determinant
of blood glucose homeostasis.

The optimal diet for MIR is a moderate fat content which is high in
mono-unsaturated fatty acids (HMUFA) with a macronutrient breakdown of 38 E%
from fat (20% MUFA, 10% PUFA, 8% SFA), 48 E% from CHO (35% complex), and 14 E%
from protein (35-40% plant protein) (8). The optimal diet for LIR is low in
fat, high in protein (LFHP) and increased fiber with a macronutrient breakdown
of <28 E% from fat (10% MUFA, 10% PUFA, 8% SFA), 48 E% from CHO (35% complex),
and 24 E% from protein (35-40% plant protein), and an additional supplement of
6-12g of soluble fiber per day. The dietary intervention will be supported by
products from industrial partners (e.g. extra virgin olive oil, high
protein-low fat products, high fiber supplements, etc.).

The dietary intervention will be employed using freely available commercial
food products. In addition, some products (which will also be commercially
available) will be provided by industrial partners and distributed at the
university. To ensure that the main fat source for the HMUFA diet is MUFA,
olive oil will be given to the participants. Additionally, a commercially
available fiber supplement will be provided and low fat foods (cereals,
legumes, pasta, etc.) will be advised to the participants receiving the LFHP
diet. The metabolic phenotype will be blinded for the participants and
researchers, thus it is unknown whether the provided diet is optimal or
suboptimal.

The general interest of this study is to obtain insight into the metabolic and
lifestyle determinants of postprandial blood glucose responses and to establish
the effect of macronutrient manipulation of a 12-week dietary intervention on
blood glucose homeostasis in metabolically different subgroups and its
relationship to physical and mental performance and well-being. Participants
may have personal health benefits if intervention effects are according to
expectations. Following the study completion, all participants will have access
to all results of the testing performed. These data can provide information
about their health status and additional information about their metabolic
phenotype, which may positively impact their health.

Participants can experience burdens such as time spent for the study.
Participants will have to invest approximately 40 hours in the study, plus an
additional 20 hours for the subgroup at UM. The dietary and healthy regimen
they will follow can be considered a burden, but also an overall health benefit
as both diets are considered healthy diets. Also the collection of fecal and
urine samples can be experienced as a burden (collecting the samples storing
them at home for up to 24 hours).

The MRI scan does not have any risks associated with it, however some patients
can experience claustrophobia. The MRI is only six minutes in Maastricht, which
is a significant reduction of a normal MRI scan time, therefore this effect is
minimized. Although scanning time at WUR is longer (30 minutes), we will check
beforehand whether participants ever experienced claustrophobia.

In addition, participants will undergo a DXA scan. Thereby, they will receive a
total radiation dose of <20 µSv (calculated by Heleen Huyten-Erkens, Radiation
Expert, Randwyck, Maastricht). The average dose of each person in the
Netherlands is 2,5 mSv per year, therefore the dose of the radiation can be
neglected (statement by Heleen Huyten-Erkens, Radiation Expert, Randwyck,
Maastricht).

The placement of the CGM and ActivPAL, though quite non-obtrusive, can be
considered a burden for the participants. The placing of each piece of
equipment will be done by experienced researchers and will be secured by
well-practiced measures to minimize issues the participant may encounter. The
calibration of the CGM may be considered a burden due to the fingerprick that
is required four times a day by a glucose meter.

During the test days, blood will be collected via a venous catheter.
Venipunctures can occasionally cause a local hematoma or bruise to occur. Some
participants report pain during venipuncture. During visit 3, an adipose
tissue biopsy will be taken. The adipose tissue biopsy might cause a local
hematoma. The UM subgroup, visit 4, will require a skeletal muscle biopsy.
After the muscle biopsy, some participants report pain, which is experienced as
muscle pain. More often the muscle feels stiff for a couple of days after the
biopsy. To minimize the risk for a hematoma, the area where the biopsy was
taken will be compressed for approximately five minutes after placing the
steristrips and a waterproof bandage. The place of incision will leave a small
scar (~3 mm for adipose tissue biopsy and ~8 mm for skeletal muscle biopsy).
During the hyperinsulinaemic-euglycemic clamp there is a small risk of hypo- or
hyperglycemia. However, from our own extensive experience, these conditions do
not occur very often and can be reversed immediately. A medical doctor is
always available during the clamp. Concerning the other study procedures (OGTT
and indirect calorimetry), there are no known risks and these measurements are
routinely applied in human biology research. Standard operating procedures
(SOPs) for each measurement are available on the UM Human Biology Department*s
server.