Methionine-Restriction Diet (MRD) in Obese Adults With Metabolic Syndrome
Methionine-Restriction Diet (MRD) in Obese Adults With Metabolic Syndrome
The purpose of this study is to determine if limiting dietary methionine (MET), one of the 10
 essential amino acids (which make up proteins), causes weight loss and/or improves glucose
 metabolism.
Methionine deficient diets have been shown to increase metabolic rate, decrease weight and
 extend lifespan in rodents. A methionine deficient diet has been tested for 17 weeks in
 humans without adverse events and with an average weight loss of 8 kg. This study will test
 the ability of a low methionine diet to cause weight loss and improve the metabolic syndrome.
 The metabolic syndrome is driven by insulin resistance which is associated with abdominal
 fat, so this study hopes to reduce visceral fat, body weight and improve insulin resistance.

 Twenty-four healthy males or females 21 to 60 years of age, inclusive with a stable weight
 and a waist circumference >40" in men and >35" in women will participate in this study.
 Subjects will need at least two of the following: 1) HDL cholesterol < 40 mg/dL in men or <
 50 mg/dl in women; 2) triglycerides > 150 mg/dL, 3) blood pressure >130/85 mmHg; 4) fasting
 glucose 110-125 mg/dL. Subjects who have diabetes, a history of heart attack, stroke, have
 had cancer in the last five years or take chronic medication for a significant illness will
 be excluded.

 Subjects will have a medical history, physical examination, chemistry panel, complete blood
 count (CBC), electrocardiogram, DEXA, abdominal CT scan to quantitate visceral fat, and blood
 will be sent to Orentreich for glucose, insulin, C-peptide, lipid profile with particle size,
 free fatty acids, adiponectin, leptin, high-sensitivity C-reactive protein, and insulin-like
 growth factor-1. Subjects will also undergo a hyperinsulinemic, euglycemic clamp to
 quantitate insulin resistance during an 18 hr inpatient stay, and will spend 24 hours in the
 metabolic chamber to measure metabolic rate. Subjects will then be placed on a diet of
 Hominex-2, a drink that will give them their protein in an amount based on their body weight,
 and they will see a dietitian who will give them a list of food they can eat consisting
 mainly of fruits, vegetables and a small amount of grains. Calories will not be restricted
 and subjects will receive a choline supplement of 500 mg/d. Subjects will be randomized to
 receive capsules containing methionine or placebo based on their body weight. The two groups
 will be on 2mg/kg/d or 23 mg/kg/d of methionine.

 Participants will return to PBRC every 2 weeks throughout the 16-week diet period to meet
 with the dietician, have weight and vital signs recorded, and have fasting blood drawn every
 4 weeks to be sent to Orentreich for compliance measures.

 The physical exam, multi-slice CT scan, DEXA, inpatient admission for euglycemic
 hyperinsulinemic clamp, metabolic chamber stay, and the blood testing obtained at screening
 and baseline will be repeated at the completion of the 16 week diet period.

 There are no known risks to the low methionine diet, but some people may have
 gastrointestinal upsets when they change their diet. The risk of the CT scan is exposure to
 x-radiation equivalent to a front and side view chest x-ray. The risk of the DEXA is the
 exposure to x-irradiation equivalent to spending 12 hours in the sunshine. There are no risks
 to staying in the metabolic chamber. The hyperinsulinemic, euglycemic clamp could cause low
 blood sugar. This will be avoided by frequent monitoring of blood sugar, and if the low blood
 sugar were to occur, the test would be stopped and sugar given through the intravenous line.
 The testing of blood involves the discomfort of a needle going into an arm vein, bruising and
 rarely fainting or infection. These risks will be minimized by trained technicians using
 sterile needles.
Inclusion Criteria:

 -  Male or female between the ages of 21 to 60, inclusive

 -  Waist greater than 40 inches for men and 35 inches for women

 -  Weight has been stable for at least 6 months (no more than 5 pounds gained or lost)

 -  For women of childbearing potential: subject must be willing to use acceptable form of
 contraception (pill, condom, diaphragm etc.)

 -  At least 2 of the following:

 HDL cholesterol

 -  Men < 40 mg/dL

 -  Women < 50 mg/dL Triglycerides ≥150 mg/dL Blood pressure ≥130/≥ 85 mmHg Fasting
 glucose ≥110-125 mg/dL

 Exclusion Criteria:

 -  Type 1 or Type 2 diabetes

 -  History of heart attack or stroke

 -  Pregnant or breastfeeding or planning to become pregnant during the study

 -  Cancer (other than non-melanoma skin) within the last 5 years

 -  Significant illness requiring medication

 -  Inability to read and follow directions in English

 -  Donated blood in the last 2 months.