Isocaloric Dietary Interventions for Insulin Resistance and the Metabolic Syndrome
Isocaloric Dietary Interventions for Insulin Resistance and the Metabolic Syndrome
In recent decades, the prevalence of obesity has increased dramatically in the United States.
 Obesity has been associated with an increased risk of the metabolic syndrome, which is
 characterized by a cluster of metabolic derangements, including insulin resistance, high
 blood sugar, high triglycerides, low high density lipoprotein (HDL) cholesterol levels, high
 blood pressure, and inflammation. Lifestyle interventions, including dietary modification,
 physical activity, and weight loss, form the basis of treatment for individuals with the
 metabolic syndrome. However, the optimal composition of the diet is not known at this time.
 Furthermore, due to hormonal and metabolic changes that accompany weight loss, most people
 find it very difficult to maintain significant weight reductions over time. As a result,
 weight regain is exceedingly common.
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