The Effects of a Moderate Weight Loss on Insulin Resistance

In this study, we will examine whether a small weight loss in lean, insulin-resistant
offspring of type 2 diabetic patients will improve insulin resistance. The control group will
consist of subjects matched for gender, age and body weight with no family history of
diabetes. Before and after weight loss, rates of basal and insulin stimulated whole body
glucose metabolism will be measured using [6,6-2H] glucose during a 3 hour basal period and a
4 hour euglycemic hyperinsulinemic (20 mU/m2-min) clamp. Rates of whole body lipolysis will
be determined using [2H5] glycerol, localized rates of lipolysis will be measured using the
microdialysis technique and muscle PI 3-kinase activity will be assessed in muscle biopsies.
FFA metabolites (fatty acyl CoA, ceramides, diacylglycerol) will be measured in fat tissue
collected from the abdominal subcutaneous fat cell depot. Body composition will be determined
with bioelectrical impedance and whole body MRI; IMCL will be measured with MRS. Before and
after weight loss, insulin secretion will be measured with the hyperglycemic clamp (as
described under Day 2 Hyperglycemic Clamp).

Inclusion Criteria:

- Healthy, sedentary, non-smoking and not taking any medications other than birth
control pills.

- Hematocrit >35%

- Subjects will have no systemic or organ disease including diabetes.

- Subjects will have no history eating disorders.

- Women must be using a form of birth control (sexual abstinence, birth control pills,
Norplant, IUD or condoms) and will be studied between day 0 and 7 of their menstrual
cycle.

- Those who are taking birth control pills or have had a hysterectomy may be studied at
any time.

- Physical activity will be assessed using a standard questionnaire with an activity
index cut off at 2.3.

Exclusion Criteria:

- Any subject, who does not fit the inclusion criteria. Including history of eating
disorders, any systemic and organ disease including diabetes.

Lactose intolerance Any blood count, clotting abnormalities HYpertriglyceridemeia (TG over
100 mg/dL)

- Hematocrit <35%.

- Women of childbearing potential, who are not using contraception (as mentioned above)
or who are not abstinent.

- Subjects who have a regular exercise regimen will not be enrolled.

- Metal implants and/or body piercing, which cannot be removed before the MR studies.