Prevention of diabetes through lifestyle intervention and population studies in Europe and around the world

Type II diabetes, is one of the fastest growing chronic diseases worldwide.
This is primarily due to increasing prevalence of obesity, caused by a
sedentary and inactive lifestyle and general food abundance. It is estimated
that in year 2000 there were approximately 150 million individuals with type II
diabetes and that this number is likely to double by 2025.The relative risk of
getting type II diabetes rises exponentially with increasing body mass index
(BMI) and already at a BMI above 23 kg/m2 the risk of getting type II diabetes
doubles. During the past 20 y, the US has experienced a surge in overweight and
obesity, and the increase in incidence of type II diabetes has paralleled these
conditions. Persons with diabetes have a 2-4 times higher risk of dying from
heart diseases compared with persons without diabetes and overall, the health
and economic costs related to the increased numbers in both young, adults and
the ageing population are huge.
The global increase in the prevalence of obesity is most likely driven by a
simultaneous increase in global food abundance incl. food of reduced
nutritional quality, together with increased sedentariness and decreased
physical activity during work and leisure time. Recent studies have also
indicated that a deviation of normal sleeping pattern (7-8 h sleep per night),
particularly short sleep, increases appetite and promotes obesity and its
related diseases (e.g. type II diabetes and cardiovascular diseases).

It is recognized now that many of the adult morbidities associated with
metabolic disease originate in childhood. An increasing number of Dutch and
children around the world are laying the foundations for metabolic disease by
being overweight, a well known predisposing factor for co-morbidities such as
type 2 diabetes, liver disease and cardiovascular disease. This increasing
prevalence of obesity in children poses a tremendous threat for future
generations and an enormous economic burden, especially considering the fact,
that childhood obesity is one of the biggest risk factors for adult obesity.

There are generally two ways to prevent type II diabetes:
1) By preventing weight gain and type II diabetes in the general population
(population-approach)
2) By preventing type II diabetes in at-risk individuals (pre-diabetics) by
weight loss and maintenance.

Main drivers in both situations are changes in dietary and physical activity
patterns, but also sleep and stress may be important factors. Unfortunately,
despite convincing evidence from clinical trials that type II diabetes can be
prevented or delayed through intensive lifestyle interventions resulting in
weight loss, the reality is that weight regain and incremental weight *creep*
are very common and jeopardise diabetes prevention. The recent FP6 DiOGenes
Study (Diet, Obesity and Genes) identified two dietary factors that were
associated with shorter-term prevention of weight regain after prior weight
loss: higher protein intake and lower glycemic index (GI). The findings showed
that overweight and obese participants assigned to the combination of modestly
higher protein and lower GI ad libitum had significantly better completion
rates and weight maintenance after 6 months as compared with the official
dietary guidelines. Indeed, those consuming the high protein-low GI combination
diet continued to lose weight during the weight maintenance phase and were
twice as likely to have maintained a 5% weight loss compared to the other
groups. On this basis, we hypothesize that the same diet may be superior to
conventional diets (i.e. those currently recommended by public authorities) for
both diabetes prevention and the reduction of its complications.

Although the positive role of physical activity in prevention of type II
diabetes has been well established, especially the role of exercise intensity
is unclear. Moreover, the data on physical activity use in connection with
lowered carbohydrate intake is very limited.

There are a few important mediating variables, which are understudied when
assessing the relationship of diet, exercise and risk for type 2 diabetes:

1. Age
An important lack in the literature is insight into potential interaction
between age and prevention of type II diabetes. It is not known whether the
proposed strategies are equally effective in young, adult and ageing
individuals. Obesity tends to *track* from childhood to adulthood. It was shown
that measures of childhood and adolescent body composition were good predictors
for body composition throughout the lifespan. Therefore, early intervention was
suggested as a key factor in tackling the obesity epidemic.

2. Sleep
Based on the literature we can assume an interaction between obesity, diabetes
and sleeping pattern. Especially sleeping behaviour in children has changed
tremendously in the last decade with more TV*s and computers available in
bedrooms and less physical activity. Both, short sleep duration and a lack of
sleep quality are associated with appetite. Only one night of sleep
fragmentation, resulting in reduced REM sleep causes an unfavorable shift in
insulin concentrations, while GLP-1 (a satiety hormone) levels and fullness
scores are reduced and ghrelin (a hunger hormone) concentrations are elevated.
These results show how reduced sleep and sleep quality may contribute to
increased food intake and insulin resistance.

3. The brain
In human research, the existence of brain insulin resistance along with
peripheral insulin resistance was suggested after the observation of a
reduction in insulin-induced changes in the global cerebral metabolic rate for
glucose in insulin resistant research participants compared to insulin
sensitive participants. Given that insulin is an important satiety signal not
only in the homeostatic system but also in the brain reward center, insulin
resistance was associated with un-inhibited activity in those centers, leading
to overeating and increased hunger perception.

The primary goal of PREVIEW is to identify the most efficient lifestyle pattern
for the prevention of type-2 diabetes in a population of pre-diabetic
overweight or obese individuals. This will be done by conducting a
multi-centre, multinational, clinical randomized intervention trial of 3 year
duration with a total of 2200 pre-diabetic participants, including children and
adolescents, adults and elderly, 315 of which will be investigated at the
Maastricht University.

The study will consist of a main study (RCT), investigating the interaction of
protein intake and physical activity on incidence type 2 diabetes and several
substudies, examining the role of the mediating variables for the outcome of
the main study. Maastricht University will take part in the multicenter
mainstudy, conduct four site-specific subsidies (all n = 40), and take part in
one multicenter substudy. More specifically, one substudy will investigate
children (n = 40) to identify the mediating role of sleeping patterns (sleep
quality and duration) for the main study outcome. One substudy will investigate
adults to identify the role of the brain, one other sub-study the role of
liver-fat, for the outcome variable *incidence of type 2 diabetes*, and one
substudy will assess the study conditions in a controlled manner in a
respiration chamber setting with regard to substrate metabolism, sleep, hunger,
satiety and cardiovascular markers . Participants in the substudies will differ
in only one condition. For brain plasticiy as well as liver fat 40 participants
in the moderate physical activity condition will be compared based on medium
vs. higher protein intake. In a 36 hour respiration chamber study a total of 40
participants (20 from each protein intervention) the effect of protein will be
assessed with regard to substrate metabolism, sleep, cardiovascular risk, and
hunger and satiety hormones.
The substudy in children will compare the moderate vs. higher protein condition
in a group with moderate physical activity intensity. For the multi-center
substudy on VO2 max 40 adults with moderate protein will be compared based on
moderate vs. high intensity physical activity.
Children and adults will be treated differently for the purpose of the main
study. This will be further specified below.

1) To determine the preventive effect of a higher protein-low GI vs. medium
protein higher-GI diet in combination with either moderate or high intensity
physical activity on the incidence of type 2 diabetes in predisposed,
pre-diabetic children, young, and older adults (both genders). This will be
done by conducting a randomized, controlled, multicentre trial (RCT) among
participants at high risk of developing diabetes (i.e. overweight with BMI > 25
kg/m2 and increased diabetes risk factors). The trial will be performed
worldwide including 6 EU nations: Bulgaria, Denmark, Finland, Spain, the
Netherlands, United Kingdom, and in Australia and New Zealand.
* Our hypothesis is, that the interaction of the higher-protein/ high intensity
physical activity condition will be superior to other combinations of protein
intake and physical activity intensities regarding the prevention of type 2
diabetes.

Objective of the sub study in children:

2. To evaluate the role of sleeping pattern for the effect of the moderate
vs. higher protein diet on insulin sensitivity in children with moderate
intensity physical activity
* Our hypothesis is that the higher protein diet may improve the sleeping
architecture, sleep quality, and sleep duration, leading to improved levels of
insulin sensitivity.

Objective of the sub studies in adults:

3. To evaluate the role of the brain, and liver fat for the effect of
moderate vs. higher protein diet on incidence of type 2 diabetes in adults with
moderate physical activity.
* Our hypothesis is that the higher protein diet decreases the activity of
brain reward pathways in response to visual food/ non-food cues and thus reduce
overeating in the absence of hunger.
* Our hypothesis is that the higher protein diet will reduce liver fat and
thereby decrease the incidence of type 2 diabetes.

4. To evaluate the role moderate vs higher intensity physical activity on
VO2max in adults with moderate protein intake.
* Our hypothesis is that the higher intensity physical activity will improve
VO2max and thereby decrease the incidence of type 2 diabetes.

5. To evaluate the role of moderate vs high protein intake on substrate
metabolism, sleep, cardiovascular risk and hunger and satiety participants will
stay in the respiration chamber for 36 hours.
* Our hypothesis is that the higher protein intake will affect all aspects in a
stronger way than the medium protein intervention.

1. Design Main study adults
The study will be carried out as a 3-year (156 weeks) multi-center, randomized,
clinical intervention trial in 8 sites in different countries. The study
consists of two distinct parts, namely an 8-wk weight-reduction period (same
for all adult participants regardless of intervention group assignment),
followed by a 148-wk randomized weight-maintenance intervention. The first part
is preceded by screening and randomization of eligible participants. Subjects
are randomized into four groups and a total of 2,500 eligible participants are
included (with an approx. screening of 5000 people) in two age-cohorts: 1)
younger adults (25 * 54 y, n=800), and 3) and older adults (55 * 70 y, n=1500).
Furthermore, 200 children (10 * 18 y) will be recruited (for child-specific
study design see 3.3) It is the plan to recruit an equal number of participants
(n = 310-15) from each of the 8 study sites. The MUMC+ will contribute 135
children and 215 adults to the PREVIEW study. Adults will be recruited from all
8 sites. Adult participants with successful weight reduction (at least 8% of
initial body weight, estimated 75% of the number of recruited particpants) will
continue into the weight maintenance phase of the study.
.
The main assessment points after the screening visit (clinical investigation
days, CID) are at the following weeks:
* Week 0 (CID1, baseline, start of weight reduction with LCD)
* Week 8 (CID2, end of weight reduction/start of randomized intervention)
* Week 26 (CID3, 6 months from baseline and 4 months after randomization)
* Week 52 (CID4, 12 months from baseline and 10 months after randomization)
* Week 78 (CID5, 18 months from baseline and 16 months after randomisation;
lightened protocol)
* Week 104 (CID6, 24 months from baseline and 22 months after randomization)
* Week 156 (CID7, 36 months from baseline and 34 months after randomization /
End of Trial, (EOT))

The 8-week run-in weight loss phase on a low calorie diet (LCD) providing
800-1000 kcal/d will precede randomization. LCD will be provided by Cambridge
Weight Plan ®. Those who achieve the target weight loss of equal or more than
8% of initial body weight will be included in the second phase (75% from the
recruited subjects, as being estimated).
The second phase will consist of 148 weeks of weight maintenance. The weight
maintenance period participants will be centrally cluster randomized for both,
the dietary and physical activity arms. Participants will be instructed to
maintain their weight loss, though further weight reduction will be allowed.
After the trial participants can follow the advise on their own terms but do
not get any supervision anymore, since the project is over.
The four study groups include:
1. Higher protein (25 E%), Moderate carbohydrate (45 E%), Low GI (<50) diet
2. Moderate protein (15 E%), High carbohydrate (55 E%), Medium GI (>56) diet
3. High-intensity physical activity (> 6 MET) Group 1: HP-HI Group 3: MP-HI
4. Moderate-intensity physical activity (3-6 MET) Group 2: HP-MI Group 4:
MP-MI

The abbreviations refer to the dietary regimen (HP/MP) and to the intensity of
physical activity (HI/MI).
MET = Metabolic equivalent of task (energy expenditure compared to resting
energy expenditure). Note that the MET*s may vary on individual basis because
of variation in fitness (intensity is always relative to a participant*s
maximal fitness). Participants will be approached up to three years after the
study via email to inquire about their diabetes status, by means of a little
questionnaire. Participation is voluntary. The purpose of this approach is to
assess the long term effects of the intervention and increase statistical power
with regard to the primary endpoint of the study, type 2 diabetes.

2. Design Sub-studies adults (brain imaging, physical fitness, body fat
distribution, and respiration chamber)
Subgroup of n = 50 adults will participate in a repeated measures design for
functional imaging (fMRI), a subgroup of n=50 for determination of fitness
(VO2max) and a subgroup of n=50 for body fat distribution, especially liverfat
(MRS). A subgroep of 50 participants is needed to determine substrate
metabolism in the respiration chamber. Participants will come for a total of
three times (except for the respiration chamber study which requires only one
appointment) throughout the main study period (baseline, after weight loss at
week 26, and after weight maintenance at week 104) to assess changes in brain
reward response to visual food cues, have their physical fitness assessed or
their liver fat content. For specification of methodology see study procedures.
Inclusion of participants will be based on treatment groups: all participants
from the main study will be asked if they are willing to participate. Those who
are interested will be stratified based on age and gender (for fMRI and for
MRS) comparing moderate vs. higher protein, both in the presence of moderate
intensity physical activity. For the comparison regarding VO2 max, participants
will be stratified based on age and gender. Only participants with moderate
protein intake will be compared with respect to moderate vs. high intensity
physical activity.


3. Design Main study children
The study in children and adolescents (10 - 18 y, n=200) will be carried out as
a randomized clinical intervention trial, where children will be recruited from
4 sites (Maastricht University n=135, University of Copenhagen n=50, University
of Nottingham n=25, and University of Navarra n=25). Children and adolescents
will be randomized by the same principle as adults, but without any
requirements for weight loss during the weight reduction period. The goal for
children and adolescents is to maintain weight (while gaining length) during
the initial 8 weeks, thus resulting in a BMI reduction during those 8 weeks.
For the duration of those 8 weeks, participants will be advised and guided by a
trained dietician to follow a diet that is based on individually calculated
needs. All children participating at the Maastricht University will come from
the COACH program, a standard care treatment program in the MUMC+, a previous
study (the MIKADO study) conducted by the department of Paediatrics of the
MUMC+, distributing flyers at the paediatric outpatient clinic of the MUMC+, or
the childhood obesity programs of Atrium MC Heerlen or Orbis MC Sittard. After
the study children will stay part of the childhood obesity program at their
local hospital.

4. Design Sub-Study children
In a sub-group of 40 children and adolescents, age 10-18 years, sleep
architecture will be assessed for one night in the PICU (pediatric intensive
care unit), a standard measure of COACH. Changes in total sleeping time, sleep
latency, REM sleep and SWS will be related to the intervention related effects
on insulin sensitivity, respectively body-composition, waist circumference,
body-weight maintenance. Sleep architecture will be assessed with
poly-somnography. Inclusion of participants will be based on treatment groups:
all participants from the main study moderate intensity physical activity
condition will be asked if they are willing to participate. In case the PICU
does not provide enough space and polysomnography devises, the children will
spend a night in an S1 chamber of the MRUM (metabolic research unit, NOT a
respiration chamber). Then their polysomnography will be measured by an
experienced researcher, similarly to the measurement in the PICU. The
researcher will stay overnight with the children. In addition, at CID4 and CID6
children will be asked to wear an iButton for 7 days after admission to the
hospital to assess circadian rhythm.
Those who are interested will be stratified based on age and gender comparing
moderate vs. higher protein diet regarding sleep related outcomes. Measurements
of the sub-study do not exceed the measurements that are part of the standard
COACH program.

1. Dietary intervention

A. The energy restricted LCD diet (for adults only) consists of 800-1000 kcal/d
and the target macronutrient composition of the diet will be 15-20% of total
energy from fat, 35-40% from protein and 45-50% from carbohydrate. During this
period, subjects will attend five group meetings at the site-centre where their
body weight, adverse events (AE) and concomitant medication will be registered
and dietary and behavioural instructions will be given. No specific
instructions on physical activity are given during the weight-reduction phase.
All adult participants should follow their LCD until they are measured at wk 8
visit.
The weight reduction period is reinforced during group meetings led by a
dietician/weight loss counsellor. There is also a meeting on week 8, following
the CID2 (clinical investigation day 2), at which participants will be
introduced to the intervention to which they have been randomized.


B. Adult participants with at least an 8% weight loss at the CID2 visit are
allowed to start the randomized intervention phase. After the screening visit,
participants have already been randomized to one of the dietary interventions,
HP = Higher protein (25 E%), moderate carbohydrate (45 E%), starchy food items
with low GI, or MP = Moderate protein (15 E%), high carbohydrate (55 E%),
starchy food items with moderate GI.
The diets are to be consumed ad libitum with respect to energy, i.e. the
participants are not asked to count the energy content, and they are not
provided with an individual target for energy intake. However, they will be
instructed about the importance of controlling portion size of particular food
types in order to achieve the macronutrient / GI prescription, and in
self-monitoring and adjustment of portion sizes in general, in order to
maintain weight loss. They will also be advised to have a regular meal pattern.
They will be repeatedly reminded, at the group meetings, about the importance
of maintaining weight at the level achieved after the weight-reduction phase.
Additional weight reduction is allowed, but without any other means than the
study diet and physical activity regimens (e.g. LCD*s using commercial products
and/or weight-reducing drugs are not allowed in the weight maintenance period).
The idea of the food-based dietary guidelines is that both diets are planned to
be healthy and supportive for weight maintenance. This implies that the food
items with increased use have at least suggestive scientific evidence on
prevention of weight gain and/or type 2 diabetes. Respectively, foods with
decreased use have at least suggestive evidence on increasing weight gain
and/or type 2 diabetes.

The participants have group-meetings counselled by a dietician (or another
qualified experienced health-care professional) on study weeks 8 (end LCD/
beginning of the randomized intervention), 10, 12, 16, 20, 26, 32, 44, 52, 64,
78, 104, 130 and 156.

A typical group-meeting will take up to 60 minutes. The participants will be in
small groups (6-12 participants per group). Participants of the two dietary
interventions (HP and MP) will not be mixed in the group meetings. The first
part of each meeting is devoted to dietary supervision. The second part of the
meeting is devoted to physical activity. Like for diet, the two physical
activity programmes (HI and MI) are not mixed. Moreover, participants are also
encouraged to contact the site-staff if they have any questions related to
diet, physical activity programme or any other items of the study.

Dietary intake is recorded by 4-d dietary records and compliance of protein
intake by analysing nitrogen in urine.

C. All participants will be randomized to one of the two physical activity
interventions, HI = high-intensity (vigorous) or MI = moderate-intensity.
Measured heart-rate (by heart-rate monitor or palpitation) is the principle way
of determining MET-levels.
Physical activity is in general unsupervised. Hence, the participants can
choose from several options with similar level of metabolic turnover (energy
expenditure divided by resting metabolic rate, i.e., MET values). The two
physical activity interventions will have roughly similar target energy
expenditure (1000 kcal/wk), but the specific advice is based on the Centre for
Disease Control (CDC) recommendations on 75 min vigorous or 150 min
moderate-intensity physical activity weekly.
In the beginning of the weight maintenance phase (week 8), the participants,
assisted by an exercise instructor (or another experienced health-care
professional), plan their personal physical activity programme. In the group
sessions, the participants are also instructed on basic principles of
increasing physical activity. Moreover, they are taught problem-solving
techniques, that is, how to overcome urges to refrain from planned physical
activities. All physical activity sessions are planned to be at the same visit
with the dietary supervision at the site-centre.
The first month of the interventions (study weeks 9*12) is used to increase the
weekly physical activity volume to 75 min. The intensity is kept moderate in
all participants.
The next month (study weeks 13*16) is used to reach the intended prescribed
program. For the HI-groups, this means that the volume (weekly duration, i.e.,
75 min) is kept constant while the intensity is gradually increased so that in
the end of this period all physical activity sessions should have an intensity
of at least 6 METs. There will be no intensity change for the MI-group, but the
volume is gradually increased from 75 min to 150 minutes per week during this
4-week period.

For adults: The research is beneficial to the participant, given that everyone
receives treatment with the aim to loose weight and improve metabolic health
through increased physical activity. The total of 8 laboratory visits is a
tolerable amount over the time of 156 weeks. For those participating in one of
the sub-studies investigating the role of neural activity, physical fitness or
liver fat for the incidence of type 2 diabetes the burden will be somewhat
bigger, since they have 3 additional study visits. Those however will be
compensated accordingly. Blood sampling will happen on every visit for the main
study. The total amount of blood taken is minimal over the time period and
there are no extra risks associated with blood drawing other than the risk for
minor bruising.
FMRI is a non-invasive standard method to determine blood oxygenation in areas
of the brain without any significant risks (see also tandardized and approved
methods for conducting fMRI experiments involving human subjects). Brain
structures and function are visualized through the utilization of a magnetic
field.
Studies in the respiratory chamber will be conducted using standard operating
procedures. A pair of subjects will always participate in the study at the same
time and therefore they will never be alone. The subjects will be able to
contact the investigators during the entire night. In addition, they will be
able to get out of the chamber at any time they feel uncomfortable.
Vascular measurements are routine and are not expected to lead to physical side
effects.
The LCD will bear no extra risks for the participant as the macronutrient
composition and vitamins/ minerals content meet the Dutch allowance of daily
recommendation. Due to extensive experience with LCD*s in our laboratory and
support of group meetings we believe that adherence to the diet is possible,
mostly due to motivation to loose weight.
For children: All participating children are part of the COACH program at the
MUMC+ or the childhood obesity programs at Atrium MC Heerlen or Orbis MC
Sittard, or are recruited through advertisements, flyers distributed at the
paediatric outpatient clinic of the MUMC+ or via a previous study (the MIKADO
study) of the department of paediatrics of the MUMC+. The intervention program
integrates care and prevention and offers the possibility to evaluate physical
and psychological co-morbidities in children and adolescents with overweight or
obesity and long term tailored care. The aim is to improve the health of
children with overweight and to prevent passing on an unhealthy lifestyle to
the next generation. These programs are standard care treatment programs in the
participating hospitals. Children and adolescents with overweight and obesity
are predisposed to significant health problems. It is known that childhood
obesity can adversely affect almost every organ system, and if left untreated,
the major impact of childhood overweight is likely to be felt in the next
generation of adults. Therefore it is of great importance to study whether
intensive (life-style based) intervention programs should start as young as
possible, or if obesity-related pathology can even be reversed to *normal* when
the program starts at young adulthood.