• Changes in body weight and adipose tissue as determined by BMI-standard deviation score (BMI-SDS), air displacement plethysmography, and DXA scan. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  

The prevalence of overweight and obesity in children and adolescents in the United States has doubled during the past 20 years. Obesity is closely linked with development of insulin resistance and other mediators of unfavorable cardiovascular risk, such as hypertension and dyslipidemia. These obesity-related risk factors often first appear during childhood. Since obese children tend to become obese adults, such children are at increased risk for persistence of these abnormalities into adulthood and for the early occurrence of obesity-related morbidity and mortality. Obesity-related insulin resistance is also largely responsible for the recently documented rise in the incidence of Type 2 diabetes in youth. To date, there is no FDA-approved pharmacotherapy for children with obesity and insulin resistance. Metformin is a medication approved for use in adults with Type 2 diabetes that is unique in that it promotes weight loss and improves features of the insulin resistance syndrome. Preliminary studies suggest that metformin may promote weight loss in obese non-diabetic children. However, the mechanism of metformin-induced weight loss has not been elucidated. We propose to evaluate the safety, tolerability, efficacy and mechanism of metformin-induced weight loss in obese, hyperinsulinemic children aged 6-12.99 years. We will conduct a six-month randomized, double blind placebo-controlled trial of metformin. All study participants will receive nutritional consultation and advice on appropriate diet. We will study the effects of metformin on weight, food intake, energy expenditure, insulin sensitivity, and lipids. At the end of the six-month placebo-controlled trial, all subjects will be offered metformin in an open label phase for an additional six months.

• INCLUSION CRITERIA:

Good general health.

Age greater than or equal to 6 and less than 13 years.

Pre-pubertal or having at most early puberty (breast Tanner I, II or III for girls, testes size less than or equal to 8 mL for boys).

Hyperinsulinemia, defined as fasting insulin concentration greater than or equal to 15 mIU/mL. The insulin level must be greater than or equal to 15 at either the NIH Clinical Center lab or the NIDDK lab at PIMC in Phoenix.

Obesity, defined as body mass index greater than or equal to 95th percentile determined by NHANES I age and sex specific data.

Subjects must have fasting plasma glucose less than 126 mg/dl and a HgbA1C of less than or equal to 6.5%.

Females who begin menstruating (or who are at risk for pregnancy) during the study must have a negative pregnancy test and must use an effective method of contraception if they are engaging in sexual intercourse.

EXCLUSION CRITERIA:

Baseline creatinine greater or equal to 1.0 mg/dl.

Significant cardiac or pulmonary disease likely to or resulting in hypoxia or decreased perfusion.

Hepatic disease with elevated liver function tests (ALT or AST) greater than or equal to 1.5 the upper limits of normal.

An alcohol history concerning for development of hepatic toxicity.

Pregnancy.

Evidence for Type 2 diabetes, including fasting plasma glucose greater than or equal to 126 mg/dl or HgbA1C greater than 6.5%.

Weight loss of greater than 2% of bodyweight within the past 6 months.

Presence of other endocrinologic disorders leading to obesity (e.g. Cushing's Syndrome).

Individuals who have, or whose parent or guardians have current substance abuse or a psychiatric disorder or other condition that, in the opinion of the investigators, would impede competence or compliance or possibly hinder completion of the study.

Recent use (within six months) of anorexiant medications.

Individuals receiving medical treatment other than diet for hypertension or dyslipidemia.

Individuals with evidence of precocious puberty.