Sub-Study of the PREVIEW Study Australia
Sub-Study of the PREVIEW Study Australia
The aim of this study is to investigate possible enduring effects of a standard 2-month
 weight loss program on appetite regulation, bone homeostasis and muscle strength in younger
 and older adults, as well as the impact of differences in dietary composition during weight
 maintenance.
This sub-study consists of 2 parts:

 PART 1. Durability of changes in appetite and appetite-regulating hormones after weight loss
 in overweight or obese pre-diabetic adults: impact of diet during weight maintenance.

 A major reason for the failure of many lifestyle-based weight loss attempts is that the body
 responds to energy restriction and weight loss with a series of adaptive responses that
 prevent ongoing weight loss and promote weight regain (Sainsbury and Zhang 2010; Sainsbury
 and Zhang 2012). This 'famine reaction' includes increased appetite and alterations in
 circulating concentrations of gut-derived hormones that tend to stimulate appetite and
 promote fat accumulation. Recent evidence suggests that these alterations are sustained for
 as long as the lower body weight is maintained (Sumithran et al 2011). This finding - if
 validated in other populations - has enormous implications for clinical practice. For
 instance, if we know for certain that the weight loss-induced increase in appetite cannot be
 reversed without weight regain, or if we can identify those individuals for whom the increase
 in appetite does not subside, then multiple fruitless and heartbreaking efforts to lose
 excess weight via lifestyle interventions could be circumvented, and those individuals could
 immediately be channelled into more aggressive - albeit still imperfect - treatment options
 (i.e. long-term appetite-suppressing medications, bariatric surgery). If, on the other hand,
 we know that the increased appetite following weight loss does subside following a period of
 weight maintenance at the lower weight, or if we could identify those individuals for whom
 this is possible, then this information could be used to promote compliance with weight
 maintenance strategies after weight loss, with patient messages such as; "Keeping weight off
 will be difficult in the beginning, but don't give up because it will likely become easier
 with time".

 A substantial body of research shows that a diet that is higher in protein
 (Westerterp-Plantenga et al 2004) and lower in glycaemic index (Brand-Miller et al 2002) than
 the diet that is conventionally recommended for health may help people to maintain a lower
 body weight post weight loss, and that this benefit may occur by reducing the drive to eat.
 These findings raise the possibility that a higher protein and lower glycaemic index weight
 maintenance diet could be used to reduce the intensity of the famine reaction in overweight
 or obese people after completion of weight loss diets, thereby improving their likelihood of
 keeping the weight off. While there is ample research showing the benefits of a higher
 protein diet for reducing appetite, enhancing weight loss and preserving lean body mass loss
 when applied during energy restricted weight loss programs, as recently reviewed (Soenen et
 al 2013), there is relatively little work to date about the emerging benefits of a higher
 protein diet applied during a weight maintenance program after weight loss. The importance of
 this Sub-Study (Part 1) is that it not only seeks to confirm a controversial new finding that
 has potentially enormous implications for the clinical management of overweight and obesity
 (Sumithran et al 2011), it also investigates the potential benefit of a higher protein and
 lower GI diet - applied during the weight maintenance phase after a standardized weight loss
 program - to prevent the apparently permanent increase in appetite that overweight and obese
 people have been reported in one study (Sumithran et al 2011) to experience in response to
 weight loss.

 Part 1 Hypothesis:

 -  Both overweight and obese individuals will demonstrate increases in appetite and
 corresponding changes in appetite-regulating hormones in response to a standardized low
 calorie diet weight loss program, and these effects will be normalized within 4-10
 months on a weight maintenance program in overweight but not in obese individuals.

 -  In both overweight and obese individuals, a higher protein and lower glycaemic index
 weight maintenance diet after a weight-reducing diet will improve normalisation of
 appetite and appetite-regulating hormones compared to a moderate protein and moderate
 glycaemic index weight maintenance diet.

 Part 1 Aim:

 • To determine fasting appetite and fasting circulating concentrations of appetite-regulating
 hormones (ghrelin and peptide YY) after a 2-month standardized low calorie diet in overweight
 and obese pre-diabetic adults, and to determine whether any effects are attenuated by 4 and
 10 months on one of two different weight maintenance programs differing in protein content
 and glycaemic index.

 PART 2. Effect of weight loss on bone homeostasis and muscle strength in younger and older
 overweight or obese pre-diabetic adults: impact of diet during weight maintenance on
 long-term durability of effects.

 While it is generally recognised that losing excess weight helps to prevent disease
 development in younger adults, there is some controversy as to whether weight loss programs
 are indicated for the management of overweight or obesity in older adults, and if so, at what
 body mass index such programs should be implemented (Chapman 2008). It is noteworthy that
 weight loss via voluntary or involuntary means in older adults is linked to reduced function,
 reduced quality of life and increased mortality (Chapman 2008). The reason for this
 relationship is not clear, but one possibility is that weight loss programs can lead to
 significant loss of bone and lean tissues under certain circumstances (e.g. inadequate
 dietary protein, inadequate exercise), and it is unknown if these losses are recuperated.
 Given that reductions in bone density and lean body mass are risk factors for fractures and
 falls in older adults, changes in body composition in response to weight loss efforts in
 older adults could inadvertently produce negative effects. In light of the established role
 of dietary protein in the maintenance of lean tissues such as bone and muscle in older people
 or in response to weight loss (Westerterp-Plantenga et al 2012), the PREVIEW trial offers an
 invaluable opportunity to investigate the effects of a standardised weight loss program on
 bone homeostasis and muscle function (strength) in younger and older adults, as well as the
 impact of differences in diet during weight maintenance in attenuating any such effects.

 Part 2 Hypothesis:

 -  That a 2-month standardized low calorie diet weight loss program leads to reductions in
 bone mass and muscle strength in both younger and older adults, particularly in older
 adults, and that these parameters return towards baseline values within 3 years in
 younger but not in older adults.

 -  That a higher protein weight-maintenance diet improves the restoration of bone mass and
 muscle strength after weight loss in both younger and older adults.

 Part 2 Aim:

 -  To measure bone mass, bone turnover and muscle strength in younger (25-45 year old) and
 older (55-70 year old) adults before and after a standardized 2-month weight loss
 program, as well as at 6, 12, 24 and 36 months after commencement of the weight loss
 program.

 -  To compare the effects of two different weight maintenance programs differing in protein
 content on the restoration of bone homeostasis and muscle strength after a standardized
 2-month weight loss diet. The weight maintenance programs are of 10 months' duration and
 are administered immediately after the 2-month weight loss program.
Inclusion Criteria:

 -  Age 25 - 45 years and 55 - 70 years

 -  Overweight or obesity status BMI>25 kg/m2

 -  Pre-diabetes. The criteria from WHO/IDF (International Diabetes Foundation) for
 assessing pre-diabetes will be used as the formal inclusion criteria, i.e. having:
 Impaired Fasting Glucose (IFG): Fasting venous plasma glucose concentration 5.6 - 6.9
 mmol/l or Impaired Glucose Tolerance (IGT): Venous Plasma glucose concentration of 7.8
 - 11.0 mmol/l at 2 h after oral administration of 75 g glucose (oral glucose tolerance
 test, OGTT), with fasting plasma glucose less than 7.0 mmol/l. Due to potential
 between-lab variation (local assessments), HbA1c is not used as an inclusion criteria
 in the screening.

 -  Informed consent required

 -  Ethnic group - No restrictions

 -  Smoking - Smoking is allowed, provided subjects have not recently (within 1 month)
 changed habits. However, smoking status is monitored throughout the study and used as
 a confounding variable.

 -  Motivation - Motivation and willingness to be randomized to any of the groups and to
 do his/hers best to follow the given protocol

 -  Other - Able to participate at CID's during normal working hours.

 Exclusion Criteria:

 Based on interview and/or questionnaire, individuals with the following problems will be
 excluded:

 -  Medical conditions as known by the subjects: Diabetes mellitus (other than gestational
 diabetes mellitus); Significant cardiovascular disease including current angina;
 myocardial infarction or stroke within the past 6 months; heart failure; symptomatic
 peripheral vascular disease; Systolic blood pressure above 160 mmHg and/or diastolic
 blood pressure above 100 mmHg whether on or off treatment for hypertension. If being
 treated, no change in drug treatment within last 3 months; Advanced chronic renal
 impairment; Significant liver disease e.g. cirrhosis (fatty liver disease allowed);
 Malignancy which is currently active or in remission for less than five years after
 last treatment (local basal and squamous cell skin cancer allowed); Active
 inflammatory bowel disease, celiac disease, chronic pancreatitis or other disorder
 potentially causing malabsorption; Previous bariatric surgery; Chronic respiratory,
 neurological, musculoskeletal or other disorders where, in the judgement of the
 investigator, participants would have unacceptable risk or difficulty in complying
 with the protocol (e.g. physical activity program); A recent surgical procedure until
 after full convalescence (investigators judgement); Transmissible blood-borne diseases
 e.g. hepatitis B, HIV; Psychiatric illness (e.g. major depression, bipolar disorder).

 -  Medication: Use currently or within the previous 3 months of prescription medication
 that has the potential of affecting body weight or glucose metabolism such as
 glucocorticoids (but excluding inhaled and topical steroids; bronchodilators are
 allowed), psychoactive medication, epileptic medication, or weight loss medications
 (either prescription, over the counter or herbal). Low dose antidepressants are
 allowed if they, in the judgement of the investigator, do not affect weight or
 participation to the study protocol. Levothyroxine for treatment of hypothyroidism is
 allowed if the participant has been on a stable dose for at least 3 months.

 -  Personal/Other: Engagement in competitive sports; Self-reported weight change of >5 %
 (increase or decrease) within 2 months prior to screening; Special diets (e.g. vegan,
 Atkins) within 2 months prior to study start. A lacto-vegetarian diet is allowed;
 Severe food intolerance expected to interfere with the study; Regularly drinking > 21
 alcoholic units/week (men), or > 14 alcoholic units/week (women); Use of drugs of
 abuse within the previous 12 months; Blood donation or transfusion within the past 1
 month before baseline or CID's; Self-reported eating disorders; Pregnancy or
 lactation, including plans to become pregnant within the next 36 months; No access to
 either phone or Internet (this is necessary when being contacted by the instructor's
 during the maintenance phase); Adequate understanding of national language;
 Psychological or behavioral problems which, in the judgement of the investigator,
 would lead to difficulty in complying with the protocol.

 -  Laboratory screening: If all of the above criteria are satisfied, the participant is
 eligible for a glucose tolerance test (blood at 0 and 120 mins), and blood glucose
 concentrations are analyzed immediately (Haemocue). In addition full blood count,
 urea, and electrolytes may be analyzed as a further safety evaluation.

 -  ONLY IF the glucose tolerance test meets the entry criteria for the study, the
 remaining samples are sent to the local laboratory for a safety check, with the
 following exclusion criteria: Hemoglobin concentration below local laboratory
 reference values (i.e. anemia); Creatinine >1.5 times Upper Limit of Normal (local
 laboratory reference values); Alanine Transaminase (ALT) and/or Aspartate Transaminase
 (AST) >3 times the Upper Limit of Normal (local laboratory reference values); Or any
 other significant abnormality on these tests which in the investigators opinion may be
 clinically significant and require further assessment.

 -  Electrocardiography (ECG). Any abnormality which in the opinion of the investigator
 might indicate undiagnosed cardiac disease requiring further assessment (e.g.
 significant conduction disorder, arrhythmia, pathological Q waves). This is done in
 adults 55-70 years of age.

 -  After LCD phase (in adults): Failure to reach at least 8% weight reduction during the
 LCD phase. This leads to exclusion from the intervention.