Evidence for Early Defects in Insulin Sensitivity and Secretion Before the Onset of Glucose Dysregulation in Obese Youths A Longitudinal Study Cosimo Giannini, 1 Ram Weiss, 2 Anna Cali, 3 Riccardo Bonadonna, 4 Nicola Santoro, 1 Bridget Pierpont, 1 Melissa Shaw, 1 and Sonia Caprio 1 We sought to determine whether obese adolescents with high- “normal” 2-h post-oral glucose tolerance test glucose levels dis- play defects in insulin secretion and sensitivity associated with future development of impaired glucose tolerance (IGT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and insulin secretion by applying mathematical modeling during the hyperglycemic clamp in 60 normal glucose tolerance (NGT) obese adolescents, divided into three groups based on the 2-h glu- cose values (,100, 100–119, 120–139 mg/dL), and in 21 IGT obese adolescents. Glucose tolerance was reevaluated after 2 years. In- sulin sensitivity decreased significantly across 2-h glucose NGT categories, while the highest NGT category and IGT group were similar. First-phase insulin secretion decreased across NGT catego- ries, while no difference was found between the highest NGT group and IGT subjects. Second-phase secretion was similar across all NGT and IGT groups. The disposition index ( C DI) decreased across NGT categories, while no difference was observed between the highest NGT and IGT subjects. Age and C DI were the best predic- tors of 2-h glucose after two years. Across rising categories of normal 2-h glucose levels, NGT obese adolescents exhibit significant impairment of b-cell function relative to insulin sensitivity associ- ated with the development of IGT. Diabetes 61:606–614, 2012 G lucose tolerance is typically categorized as ei- ther normal (NGT) or impaired (IGT), based on 2-h plasma glucose concentration during an oral glucose tolerance test (OGTT) (1). Studies in youth have demonstrated defects in b-cell function across the spectrum of glucose tolerance (2,3). Interestingly, b-cell defects appear to be evident in individuals with high-normal 2-h glucose (4). Although recent cross-sectional clamp studies have indicated a decline in the disposition index ( C DI) in obese children with 2-h glucose below IGT levels (5), no longitudinal studies have monitored the evolution of these defects. The overall hypothesis of this study was that the 2-h glucose represents a continuum and that rising levels, even within the seemingly normal range, represent increased risk for glucose tolerance deterioration. There- fore, we tested two hypotheses: 1) that obese youths with high-normal 2-h post-OGTT glucose levels display defects in both insulin secretion and sensitivity similar to those present in IGT subjects; and 2) that subjects with the highest-normal 2-h glucose will have a greater likelihood of developing IGT over time. We tested these hypotheses through mathematical modeling of insulin secretion during a hyperglycemic clamp in NGT obese adolescents strati- fied into three levels of 2-h glucose values and in a group of IGT obese youths. Glucose tolerance in NGT subjects was evaluated longitudinally. RESEARCH DESIGN AND METHODS Subjects were recruited from a multiethnic cohort participating in the Yale Pathophysiology of Type 2 Diabetes in Youth Study, a long-term project aimed to study early alterations in glucose metabolism in obese youth (4). The study was approved by the Human Investigations Committee of the Yale School of Medicine. In order to be eligible, subjects needed to be obese and not be taking medications that affect glucose metabolism. In addition to parental consent, complete medical histories and thorough physical examinations were obtained from each participant. Stage of development was assessed on the basis of breast development in girls and genital development in boys according to Tanner criteria. All subjects were negative for autoimmune markers for type 1 diabetes (insulin antibody, GAD65, and islet cell antibody 512). Study population: cross-sectional data in the entire cohort. A multiethnic cohort of 1,601 obese Caucasian, African American, and Hispanic youth par- ticipated in the study (Supplementary Table). All subjects underwent a single OGTT and 80.2% were NGT (fasting plasma glucose ,100 mg/dL and 2-h glu- cose ,140 mg/dL) and 19.8% were IGT (140 mg/dL #2-h glucose #199 mg/dL). The distribution of 2-h glucose levels in NGT and IGT subjects was evaluated. In addition, according to the 2-h glucose levels, NGT subjects were divided into three groups: 1) less than 100 mg/dL, 2) 100–119 mg/dL, and 3) 120–139 mg/dL (4). In a previous study, we found the results from the OGTT to be reproducible because intraindividual variability was low in obese youth (6). Study population in the subgroup analysis: cross-sectional and longitudinal data. As part of the Yale Pathophysiology of Type 2 Diabetes in Youth Study, all subjects were offered a hyperglycemic clamp and a hyperinsulinemic- euglycemic clamp at baseline. Only those who participated in both clamp studies (60 NGT and 21 IGT) were included in this analysis. Cross-sectional data on 30 subjects from both the hyperglycemic and euglycemic clamp have been previously reported (2,7). Clinical and anthropometric characteristics of the subgroup were similar. NGT subjects in the subgroup were also divided into three groups based on the 2-h glucose values. A subgroup of 21 obese IGT subjects who underwent a similar study paradigm was used to compare the magnitude of differences in insulin sensitivity and secretion across categories of NGT and IGT. After a follow-up period of ;27 months, 75 out of 81 subjects (55 NGT and 20 IGT) performed a second OGTT. The time interval was based on our previous study suggesting that changes in categories of glucose tolerance in obese adolescents are likely to occur over a relatively short period of time (8). During From the 1 Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut; the 2 Braun School of Public Health and Community Medicine, Hadassah Faculty of Medicine, Hebrew University, Jerusalem, Israel; 3 Eli Lilly and Company, Basingstoke, Hampshire, U.K.; and the 4 De- partment of Medicine, Division of Endocrinology and Metabolic Diseases, University of Verona, Azienda Ospedaliera Universitaria Integrata di Verona, Ospedale Civile Maggiore, Verona, Italy. Corresponding author: Sonia Caprio, sonia.caprio@yale.edu. Received 14 August 2011 and accepted 23 November 2011. DOI: 10.2337/db11-1111 This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db11-1111/-/DC1. Ó 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying commentary, p. 562. 606 DIABETES, VOL. 61, MARCH 2012 diabetes.diabetesjournals.org ORIGINAL ARTICLE Downloaded from http://diabetesjournals.org/diabetes/article-pdf/61/3/606/560851/606.pdf by guest on 22 August 2023