Isocaloric Dietary Interventions for Insulin Resistance and the Metabolic Syndrome

Several dietary patterns, including the Dietary Approaches to Stop Hypertension study diet
(the DASH diet) and the low glycemic index diet (low GI diet), may be useful in the
treatment of individuals with the metabolic syndrome, even if body weight stays the same.
Novel findings from our own pilot study suggest that these dietary patterns may improve
insulin resistance and some other features of the metabolic syndrome, even after just two
weeks and in the absence of weight loss. In this important follow-up study, the metabolic
effects of the DASH diet and the low GI diet will be compared to those of an Western-style
control diet. At least 39 overweight, insulin-resistant volunteers with the metabolic
syndrome will be studied during a 32-day inpatient admission. All food will be provided, and
body weight will be kept stable throughout the study. Subjects will first undergo testing
after consuming a Western-style diet for two weeks. They will then be randomized to one of
three study diets: the DASH diet, the low GI diet, or the Western-style diet. Testing will
again be conducted after 2 weeks of weight stability on the study diet. Testing will include
the assessment of insulin sensitivity and other metabolic parameters, such as blood sugar
and cholesterol levels, blood pressure, and inflammation. This study will provide important
information about the effects of these promising dietary patterns on features of the
metabolic syndrome, in the absence of weight loss.

Inclusion Criteria:

1. Nonsmoking men and postmenopausal women, ages 18 - 65. Premenopausal women who would
not be expected to have significant fluctuations in estrogen and progesterone levels
during the study (e.g. those on continuous monophasic hormonal contraception) may be
included in the study at the discretion of the PI or designated study staff.

2. Body mass index (BMI) of at least 27 kg/m2

3. Body weight < 200 kg (the weight limit of the Bod Pod® scale)

4. Evidence of insulin resistance, as suggested by any one of the following:

- Fasting glucose of 100 mg/dL or higher

- Impaired glucose tolerance, with a glucose concentration of 140 mg/dL or higher,
2 hours after a 75-gram oral glucose challenge.

- A fasting insulin concentration of 9 mIU/L or higher

5. Willingness to consume only study food and drink for the duration of the study

6. Willingness to be randomized to any one of the three study diets

7. If applicable, willingness to maintain consistent intake of coffee and/or tea during
the inpatient periods (due to the potential effects of these drinks on inflammatory
markers)

8. Willingness to avoid the use of all over-the-counter or prescription vitamins,
dietary supplements, and herbal products during the study. At the PI's discretion,
other nutritional supplements, such as iron, may also be continued during the study
if they are deemed medically necessary and are unlikely to influence study results.

9. If applicable, willingness to continue current antihypertensive medications
(especially angiotensin converting enzyme inhibitors and angiotensin receptor
blockers, which may affect levels of inflammatory markers) at the same dose and
schedule throughout the study,unless a change is advised by the subject's primary
care provider or the study investigators

10. Willingness to avoid the use of non-steroidal anti-inflammatory drugs (NSAIDS),
including low-dose daily aspirin, throughout the inpatient admission, (due to the
potential effects of these agents on inflammatory markers).

11. at least two of the following:

- waist circumference greater than 35" in women or 40" in men

- blood pressure greater than 120/80 mmHg but less than 150/90 mmHg (on 2 blood
pressure medications or less)

- triglyceride level greater than 150 but less than 500 mg/dL

- HDL ("good") cholesterol less than 40 mg/dL in men or 50 mg/dL in women

Exclusion Criteria:

1. Current tobacco smoking

2. History of a bleeding disorder

3. Known or suspected cardiovascular disease, including angina, myocardial infarction,
medical or surgical treatment for atherosclerotic disease, arrhythmia, or congestive
heart failure

4. Blood pressure higher than 145/90 after 10 minutes of rest, confirmed on two or more
visits, or treatment with three or more antihypertensive agents at any blood
pressure. Subjects taking up to two antihypertensive agents may be included in the
study if 1) BP is at least 115/75 mmHg but < 145/90 mmHg on these agents and 2) they
agree to remain on the same medications (and same dosages) during the study, unless
otherwise advised by a primary care provider or study investigators (e.g. the dosage
may be reduced or the medication may be stopped if signs or symptoms of hypotension
develop during the study)

5. Fasting glucose > 165 mg/dL, glycosylated hemoglobin > 8%, or any treatment with oral
hypoglycemic agents, insulin sensitizing agents (e.g. metformin or
thiazolidinediones), insulin, incretin mimetics (e.g. exenatide), amylin analogues
(e.g. pramlintide), or endocannabinoid receptor antagonists (e.g. rimonabant).
Volunteers with type 2 diabetes and a glycosylated hemoglobin level of 7.5% or higher
will be encouraged to discuss treatment options (e.g. pharmacotherapy versus study
participation) with their primary care providers before enrolling in the study

6. History of chronic glucocorticoid use, oral glucocorticoid use for more than 5 days
in the previous year, or anticipated treatment with oral or intravenous
glucocorticoids during the study period. Daily, low-dose, inhaled or nasal
glucocorticoids may be acceptable in some cases, at the discretion of the Principal
Investigator.

7. Current treatment with over-the-counter or prescription weight loss medications, such
as orlistat or sibutramine

8. History of bariatric surgery

9. Current treatment with any cholesterol-lowering medications, such as statins,
niacin,fibrates, or ezetimibe

10. Hyperthyroidism or untreated hypothyroidism. Subjects with chronic, treated, stable
hypothyroidism may be included in the study at the discretion of the Principal
Investigator

11. Obstructive sleep apnea, or significant symptoms suggestive of this condition

12. Active gallstone disease

13. Known history of chronic hepatitis, or liver enzymes (AST or ALT) more than 2.5 times
the upper limit of normal

14. Known infection with HIV or confirmed positive test for HIV antibody

15. Inflammatory bowel disease, active cancer, or any other medical condition that may
cause significant acute weight loss or gain

16. Sustained weight loss > 5% of body weight in the previous two months, or sustained
weight loss > 10% of body weight in the previous six months

17. History of kidney stones

18. Chronic or acute renal disease

19. Serum calcium, potassium, or magnesium above the normal limit, confirmed on two
screening tests

20. Seizure disorder

21. History of any inpatient psychiatric admission within the past two years

22. History of schizophrenia, psychosis, or bipolar disorder

23. History of anorexia nervosa or bulimia nervosa, as defined in the Diagnostic and
Statistical Manual of Mental Disorders, fourth edition (DSM-IV), or a history of
medical or psychological treatment for an eating disorder

24. Severe binge eating disorder, as defined as a Binge Eating Scale score of 27 or more.
Individuals with scores of 18-26, which may be indicative of moderate eating
disturbances, will be evaluated further to determine whether moderate to severe
eating pathology actually exists. This evaluation process will be based on the
DSMIVresearch criteria for binge eating disorder. Individuals with scores of 18-26
who meet the DSM-IV research criteria for binge eating disorder will be excluded,
whereas those without significant eating pathology may be included in the study.

25. Untreated moderate to severe depression, as evidenced by a Beck Depression Inventory
score of 20 or higher at screening. Subjects with a remote history of depression or
stable, treated depression may be included in the study at the discretion of the
Principal Investigator

26. History of alcohol or drug abuse within the previous two years

27. History, physical, or laboratory findings suggestive of any other medical or
psychological condition that would, in the opinion of the principal investigator,
make the candidate ineligible for the study.

28. Any social or behavioral condition that, in the opinion of the investigator, would
interfere with adherence to study requirements