DIABETES, VOL. 48, OCTOBER 1999 2039 Insulin Resistance During Puberty Results From Clamp Studies in 357 Children Antoinette Moran, David R. Jacobs Jr., Julia Steinberger, Ching-Ping Hong, Ronald Prineas, Russell Luepker, and Alan R. Sinaiko Insulin resistance may be an important cause of a con- stellation of cardiovascular risk factors in adults, and onset of this syndrome may occur in childhood. How- ever, children normally experience transient insulin resistance at puberty. There were 357 normal children (159 girls, 198 boys) age 10–14 years who underwent euglycemic clamp studies to assess the effects of Tanner stage (T), sex, ethnicity, and BMI on insulin resistance. Insulin resistance increased immediately at the onset of puberty (T2), but returned to near prepu- bertal levels by the end of puberty (T5). Its peak occurred at T3 in both sexes, and girls were more insulin resistant than boys at all T stages. White boys appeared to be more insulin resistant than black boys; no difference was seen between white and black girls. Insulin resistance was strongly related to BMI, triceps skinfold thickness, and waist circumference, and this relationship was independent of Tanner stage or sex. Differences in BMI and adiposity did not, however, entirely explain the insulin resistance of puberty. These results demonstrate that 1) significant differ- ences in insulin resistance are present between boys and girls; 2) insulin resistance increases significantly at T2, T3, and T4, but decreases to near prepubertal lev- els at T5; and 3) while insulin resistance is related to BMI and anthropometric measures of fatness, these factors do not completely explain the insulin resistance that occurs during the Tanner stages of puberty. Diabetes 48:2039–2044, 1999 T he pattern of changes in insulin resistance during puberty and the factors influencing these changes have not been completely defined. All children become more insulin resistant at the time of puberty. While prepubertal children and postpubertal young adults are equally sensitive to insulin, adolescents are insulin resistant compared with either of these groups (1,2). Thus, insulin resistance appears to be a transient physiological stage of normal development. Insulin resistance in adults is associated with obesity, glu- cose intolerance or diabetes, hypertension, dyslipidemia, and cardiovascular disease. Although the relationship among these conditions is complex, insulin resistance may be the pri- mary initiating factor (3–5). There is increasing evidence that the onset of the insulin resistance syndrome may occur in childhood or adolescence (6,7). Before an etiologic associa- tion between insulin resistance and other cardiovascular risk factors can be considered in this age-group, a clear definition is necessary of the normal physiologic changes in insulin resistance that occur during puberty. Pubertal insulin resistance occurs during a time of profound change in body composition and hormone levels. During puberty, BMI slowly increases (8). Lean body mass and fat mass increase in both sexes, but, by the end of puberty, fat accounts for a greater percentage of total body weight in girls than boys. Increased body fat and BMI correlate strongly with insulin resistance and have been proposed as potential mediators of the pubertal changes in insulin resis- tance (2,6,9,10). However, insulin resistance can occur dur- ing puberty in the absence of changes in BMI (9). Moreover, young adult women are more sensitive to insulin than puber- tal girls, despite presumably having a greater percentage of body fat (1,2). It appears, therefore, that factors other than changes in body composition may be more important in the onset of pubertal insulin resistance. Other studies have compared insulin resistance in adoles- cents to prepubertal children and adults (1,2,6,9–12). How- ever, no study has had a sufficient number of subjects to characterize insulin resistance at each of the five Tanner stages of puberty or to define the relation within Tanner stages to sex, body size, or body fatness. The present study, in which euglycemic insulin clamps were performed on 357 normal children age 10–14 years, clarifies these relations. It represents the largest cross-sectional study to date that examines insulin resistance in the pediatric population. RESEARCH DESIGN AND METHODS Subjects. This study was approved by the University of Minnesota Committee for the Use of Human Subjects in Research. Informed consent was obtained from parents and informed assent from the children. The subjects were participants in a longitudinal study of the relation between insulin resistance and cardiovascular risk factors in children. They were randomly selected after blood pressure screening of 12,043 fifth through eighth grade chil- dren in the Minneapolis public school system in 1996 and stratified according to sex, ethnicity (black and non-Hispanic white), and blood pressure percentile (50% from the upper 25th percentiles and 50% from the lower 75th percentiles) to increase the percentage of children at potential cardiovascular risk. The per- centage of children of each race, sex, and Tanner stage was relatively evenly dis- tributed between the two blood pressure groups. Informed consent was obtained From the Department of Pediatrics (A.M., J.S., A.R.S.) and the School of Public Health (D.R.J., C.-P.H., R.P., R.L.), University of Minnesota, Minneapolis, Minnesota. Address correspondence and reprint requests to Antoinette Moran, MD, UMHC Pediatric Department Box 404, 516 Delaware St. SE, Minneapolis, MN 55455. E-mail: moran001@tc.umn.edu. Received for publication 22 April 1999 and accepted in revised form 7 July 1999. M, glucose uptake during insulin clamp; T, Tanner stage.