Fasting Hyperinsulinemia Is a Predictor of Increased Body Weight Gain and Obesity in Pirna Indian Children Olalekan E. Odeleye, Maximilian de Courten, David J. Pettitt, and Eric Ravussin Hyperinsulinemia is commonly associated with obesity, but it has not been determined which defect comes first. Some have proposed that hyperinsulinemia may precede obesity in populations prone to NIDDM, such as Pima Indians or Pacific Islanders. In contrast, longitu- dinal studies in adults show that insulin sensitivity and low fasting insulin concentrations are associated with increased weight gain, whereas insulin resistance seems to protect against weight gain. The present study examined whether fasting plasma hyperinsuline- mia is a risk factor for weight gain in prepubertal chil- dren in the Pima Indian population—a population that is prone to obesity. Fasting plasma insulin concentration was measured in 328 5- to 9-year-old Pima Indian chil- dren (147 boys and 181 girls) with normal glucose tol- erance. Follow-up weight was obtained an average of 9.3 ± 1.9 years (means ± SD) later at age 15-19 years. Fast- ing plasma insulin concentration correlated with the rate of weight gain per year in both boys (r = 0.42; P < 0.0001) and girls (r = 0.20; P < 0.01) and was associated with the rate of weight gain, independent of known determinants of weight change, i.e., initial relative weight, change in height, age, and sex. Similar rela- tionships were found between fasting plasma insulin concentration and the change in relative weight and in triceps skinfold thickness—two indicators of obesity. In conclusion, fasting hyperinsulinemia may be a risk fac- tor for the development of obesity in young children. Diabetes 46:1341-1345, 1997 O besity, insulin resistance, and hyperinsulinemia are common features of NIDDM (1) and predict the development of NIDDM in Pima Indians (2). Despite the fact that overfeeding and weight gain cause hyperinsulinemia in humans, it remains to be deter- mined whether the converse is true, i.e., that hyperinsuline- mia leads to obesity (3,4). In 1962, Neel (5) postulated that individuals predisposed to diabetes differ metabolically from those who are not and that hyperinsulinemia may precede obesity (6). Fundamen- tal to his "thrifty genotype" hypothesis is the concept that hyperinsulinemia increases efficiency of fat storage and thus From the Clinical Diabetes and Nutrition Section, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona. Address correspondence and reprint requests to Dr. E. Ravussin, CDNS- NIDDK-NIH, 4212 N. 16th St., Phoenix, AZ 85016. E-mail: eric_ravussin @nih.gov. Received for publication 29 October 1996 and accepted in revised form 9 April 1997. plays a crucial role in the development of obesity and dia- betes. Contrary to the thrifty genotype hypothesis, observa- tions in adult Pima Indians show a lower body weight gain in insulin-resistant subjects compared with insulin-sensitive subjects (7,8). Similar associations have also been observed in Hispanic and Caucasian subjects (9-11). Thesefindingssug- gest that insulin resistance and its associated hyperinsuline- mia are secondary rather than primary to obesity and that insulin resistance represents a physiological adaptation to obesity that limits further weight gain (12). However, many of these studies were carried out in adult members of popu- lations with a high prevalence of obesity and NIDDM. Such individuals may have long-standing insulin resistance and many may have developed compensatory mechanisms to overcome the initial defects, thus making it difficult to iden- tify causal abnormalities. One approach to understanding the sequence of defects preceding obesity and NIDDM is to study children genetically predisposed to obesity. Pima Indian children are hyperinsulinemic (13) with a strong genetic predisposition to obesity (14,15). The present study examined whether fasting hyperinsulinemia is a risk factor for excess body weight gain in 5- to 9-year-old Pima Indians fol- lowed for -10 years. In both boys and girls, higher baseline fasting insulin concentration was associated with higher rates of weight gain and most likely excess fat disposition, as assessed by the changes in relative weight for height and in triceps skinfold thickness. RESEARCH DESIGN AND METHODS Subjects and protocol. Data from children participating in a longitudinal study of the etiology of obesity and diabetes in the Gila River Indian Community of cen- tral Arizona (16) were examined. Analyses were restricted to all children exam- ined initially at age 5-9 years and with a follow-up examination at age 16-19 years. The initial and follow-up ages were selected to minimize the confounding effects of puberty on insulin resistance, compensatory hyperinsulinemia, and growth (17-19). Children diagnosed with NIDDM or impaired glucose tolerance at base- line examination were excluded from the analyses, leaving 328 Pima Indian chil- dren, 147 boys and 181 girls. Informed parental consent was obtained, and all pro- cedures were explained to both parents and children. The studies were approved by the Institutional Review Board of the National Institute of Diabetes and Diges- tive and Kidney Diseases (NIDDK), the Indian Health Service, and the Tribal Council of the Gila River Indian Community. For each examination, subjects were instructed to eat their habitual diet the day before the test and to refrain from eating and drinking after 9:00 P.M. They reported to the clinic at 8:00 A.M., where height and weight were measured with the subject wearing light clothing and no shoes. Relative weight for sex, age, and height was deter- mined using a reference population described by Jelliffe (20). While the children were seated, the triceps skinfold thickness was measured at the midpoint of the right arm (between the acromion and the olecranon processes), using a Lange Skinfold Caliper (Cambridge Scientific Industries, Cambridge, MD). Values were recorded to the nearest millimeter. Subjects then had a 75-g oral glucose tolerance test, and glu- cose tolerance was assessed according to World Health Organization criteria (21). DIABETES, VOL. 46, AUGUST 1997 1341 Downloaded from http://diabetesjournals.org/diabetes/article-pdf/46/8/1341/362554/46-8-1341.pdf by guest on 04 November 2022