Rosiglitazone-Induced Weight Gain

Study Design Randomized, controlled trial. Volunteers for the study will be recruited by advertisements in the local newspapers as well as through Stanford University e-mail. All studies will occur at Stanford General Clinical Research Center (GCRC).

At baseline, enrolled candidates will be required to keep a daily food and beverage record for 2 weeks as well as blood sugar log of at least 2 measurements a day (fasting and pre-dinner). Candidates will have an initial nutrition/diabetes consult with dietitian. They also will be asked to do a 24-hour urine collection once a week (2 times during the 2 week period) for quantitative assessment of glucosuria. During those 2 weeks individuals will come for GCRC outpatient visit once a week for weight, blood pressure, and blood sugar check.

After the initial two weeks, all individuals will undergo a meal profile test, after a 12-hour overnight fast, which consists of measurement of daylong plasma glucose, free fatty acids, and insulin responses to standard meals. Food for the test will be prepared by GCRC Metabolic kitchen. In order to assess the degree of postprandial and day-long hyperinsulinemia and the benefits of rosiglitazone on the metabolic abnormalities in patients with poor glycemic control, we plan to measure plasma glucose, free fatty acids, and insulin concentrations before 8 am and at hourly intervals for four hours after breakfast at 8 am and four hours after lunch at noon in response to identical test meals containing (as percentage of calories) 15% protein, 40% fat, and 45% carbohydrate. Baseline blood samples for fasting lipid and lipoprotein concentrations will be obtained after an overnight fast on the day of the meal profile. Cholesterol and lipoprotein subclasses will be analyzed by VAP-II method which is based on continuous enzymatic analysis of cholesterol and lipoprotein classes separated by a single vertical spin centrifugation using a controlled-dispersion flow analyzer. Hemoglobin A1C will be measured by an affinity chromography assay at baseline and at the end of the study.

Randomization protocol. After completion of the Meal Profile test all subjects will be started on Rosiglitazone for improvement of their glycemic control and randomized to one of the three groups (15 subjects in each group):

1. Continuation of the current diet.
2. Reduced calorie diet. Amount of reduced calories will be calculated proportionally to the calories lost via glucosuria.
3. Fixed calorie reduction diet. Reduction of daily caloric intake by 500 kcal. Rosiglitazone will be given at 4 mg for the first 4 weeks, and if tolerated, increased to 8 mg for the duration of the study. All candidates will have counseling on general meal plan with the nutritionist.

Follow-up. Subjects will be followed for 4 months. They will come to the GCRC twice a month for weight, blood pressure, blood sugar checks, and for nutrition follow-up.

End of the study measurements and clinical procedures: meal profile, lipid panel, 24-hour urine collection will be done at the end of 4 month follow-up period. Liver function tests will be done at the baseline, 4, 8, 12, and 16 weeks while on Rosiglitazone.

Outcomes: we expect to demonstrate at the end of the study that modification of the diet prevents weight gain in Rosiglitazone treated patients and to offer the optimal dietary interventions that could be applied in TZD-treated patients to minimize weight gain while effectively treating DM and insulin resistance.

Inclusion / Exclusion Inclusion criteria: 1) age between 30 and 70 years old, 2) normal chemical screening battery, 2) BMI less than 36 kg/M2, 3) non-controlled type 2 DM, defined by a fasting plasma glucose between 160 and 220 mg/dl, 4) individuals should be on a stable dose of sulfonylurea for at least one month prior to the enrollment.

Exclusion criteria: 1) liver enzymes 2.5 times above normal values, 2) chronic inflammatory, neoplastic disease, 3) subjects with clinical evidence of congestive heart failure.