The Impact of Low-fat and Full-fat Dairy Consumption on Glucose Homeostasis (DAIRY Study)

This is a randomized controlled feeding trial designed to investigate whether the consumption
of a diet rich in low-fat dairy vs. full-fat dairy vs. a limited dairy diet differentially
affects glucose homeostasis. The researchers will also begin an investigation into the
mechanisms by which dairy may affect glucose tolerance and its determinants. The
investigators will study 60 men and women with the metabolic syndrome who will consume diets
differing in their type and content of dairy foods, in a parallel-design randomized
controlled trial consisting of a 4-week wash-in diet period and a 12-week dietary
intervention period.

Subjects will be randomized using block randomization stratified by gender and insulin
resistance (low insulin resistance vs. high insulin resistance or manifest diabetes) to one
of three diet groups, which they will follow for 12 weeks: the limited dairy diet, the
low-fat dairy diet, or the full-fat dairy diet. During the dietary intervention, participants
will be provided with specific amounts and types of dairy products by the Human Nutrition Lab
(HNL) at Fred Hutchinson Cancer Research Center (FHCRC). In the limited dairy diet arm,
participants will be asked not to consume any dairy, other than three servings of nonfat milk
per week, which will be provided. In the two dairy diet arms, participants will be asked to
consume 3.3 servings per day of either nonfat/low-fat or full-fat milk, yogurt, and cheese.
Participants will be asked to consume all of the dairy products they receive, not to consume
any other dairy products for 12 weeks, and to continue consuming their habitual diet ad
libitum (i.e., to eat only when hungry, and to stop eating when comfortably satiated).

Prior to randomization, subjects will complete a wash-in diet period of 4 weeks during which
they will be asked to consume the limited dairy diet (i.e., consume 3 servings of nonfat milk
per week, and not consume any other dairy products). In the third week of the wash-in diet
period, subjects will also complete their first of two 5-day controlled feeding periods
(i.e., consume study dairy products alongside a provided standard American diet) to measure
ad libitum energy intake. During the last week of the wash-in diet period, participants will
be admitted to clinic for a baseline visit (clinic visit #1). After clinic visit #1, subjects
will be randomized to one of the three study arms, as outlined above. They will follow their
randomly assigned study diet for the next 12 weeks. In the second week of the main
intervention period, subjects will complete their second 5-day controlled feeding period to
again measure ad libitum energy intake, this time on the specific intervention diet they had
been randomized to. In the last week of the 12-week diet phase, subjects will be admitted for
the follow-up clinic visit (clinic visit #2). At both clinic visits, the researchers will
collect fasting blood; measure body weight and height, waist and hip circumference, and blood
pressure; conduct a 3-hour FS-OGTT to assess glucose tolerance, insulin sensitivity, and
pancreatic beta-cell function; conduct a whole-body DEXA scan to assess body fat mass, lean
mass, and body fat distribution; and an abdominal MRI scan to assess liver triglyceride
content and the ratio of intra-abdominal to subcutaneous adipose tissue. Subjects will also
complete five Food Frequency Questionnaires (FFQ's) and five unannounced 24-hour dietary
recalls during the study to assess dietary intakes.

The primary analysis will be a per protocol analysis that will include at least 60
participants (at least 20 in each intervention arm) who comply with all study procedures per
protocol. The investigators anticipate enrolling up to 72 participants to achieve this goal.
In a secondary analysis, the researchers will analyze the impact of the dietary intervention
on all enrolled participants, including those who dropped out, were excluded, or
non-compliant with the study protocol, in an intent-to-treat (ITT) analysis that will be
reported and interpreted together with the per protocol analysis.

Inclusion Criteria:

- Metabolic syndrome (three of the following five criteria):

- Increased waist circumference: In Asians: ≥ 90 cm in men, ≥ 80 cm in women; in
all other races: ≥ 102 cm in men, ≥ 88 cm in women

- Fasting plasma triglycerides ≥ 150 mg/dL, or drug treatment for elevated
triglycerides

- High-density lipoprotein (HDL)-cholesterol <40 mg/dL in males or <50 mg/dL in
females, or drug treatment for reduced HDL-cholesterol

- Systolic blood pressure ≥ 135 mm Hg or diastolic blood pressure ≥ 85 mm Hg or
drug treatment for hypertension

- Fasting plasma glucose ≥ 100 mg/dL or previous diagnosis of diabetes

- Body weight within 10% of current weight over the last 6 months before starting the
study

- Able to come to the FHCRC regularly to pick up food

- Able and willing to attend a study initiation meeting of ~1.5 hour duration at the
FHCRC, two clinic visits of ~5 hours duration each at the University of Washington
(UW) Medial Center Clinical Research Center (CRC), and two clinic visits of ~2 hours
duration each at the UW Bio-Molecular Imaging Center (BMIC)

- Willing to follow the dietary regimen

- Able to provide informed consent

Exclusion Criteria:

- Antidiabetic medications or insulin within the last 6 months

- Uncontrolled diabetes, defined as HbA1c > 8.0%

- Allergy to milk protein

- Presence of major chronic inflammatory or autoimmune disease (with acute symptoms or
CRP > 10 mg/L), or malabsorption syndromes

- Presence or history of liver disease or end-stage renal disease requiring dialysis

- Uncontrolled thyroid disease

- Inability or unwillingness to eat the provided foods

- Contraindications for MRI scan other than body size

- Intake of drugs likely to interfere with study endpoints, including corticosteroids,
anabolic steroids, antiretroviral drugs, anti-psychotic drugs and immunosuppressive
drugs (within 3 months of starting the study)

- Regular high-dose use of non-steroidal anti-inflammatory drugs (more than 3 times per
week and more than 600 mg per day, within 3 months of starting the study)

- Presence or recent history of anemia (within 3 months of starting the study)

- History of bariatric surgery

- Participation in an intervention study or weight-loss program (within 3 months of
starting the study)

- Alcohol intake > 2 drinks per day (within 12 months of starting the study)

- Use of tobacco products, eCigarettes, or recreational drugs on more than 2 days per
month (within 12 months of starting the study)

- Current or recent (within 12 months of starting the study) pregnancy or breastfeeding,
or intention of becoming pregnant in the next 6 months

- Fasting Triglycerides >1000mg/dL

- Any cancer other than non-melanoma skin cancer in the last 3 years

- Other significant health condition, as determined by researcher and Physician of
Record, that makes the individual unfit to participate