ABSTRACT: BACKGROUND:Type 2 diabetes is preceded by a prediabetic stage of impaired glucose tolerance that affects 10-23% of youth and is expected to double over the next decade. The natural history of impaired glucose tolerance and the determinants of ?-cell dynamic response have never been investigated longitudinally in young people. We aimed to investigate the clinical and metabolic determinants of longitudinal glucose tolerance changes and ?-cell function in a multiethnic cohort of obese youth. METHODS:We followed up prospectively a multiethnic cohort of overweight and obese (body-mass index >85th percentile) adolescents with baseline normal glucose tolerance (plasma glucose <140 mg/dL) or impaired glucose tolerance (plasma glucose 140-199 mg/dL) at the Yale Pediatric Obesity Clinic (CT, USA). All participants underwent a 3-h oral glucose tolerance test at baseline and after 2 years to estimate insulin secretion (oral disposition index) in the context of body insulin sensitivity. As part of standard care at the clinic, all participants received dietary advice and underwent dietary assessment every 5-6 months. No structured lifestyle or pharmacological intervention was administered. FINDINGS:Between January, 2010, and December, 2016, 526 adolescents (mean age 12·7 years, range 10·6-14·2) were enrolled to our study. At baseline, 364 had normal and 162 had impaired glucose tolerance. Median follow-up was 2·9 years (IQR 2·7-3·1). 105 (65%) of 162 with impaired glucose tolerance at baseline reverted to normal glucose tolerance at follow-up, 44 (27%) had persistent impaired glucose tolerance, and 13 (8%) progressed to type 2 diabetes. A feature of reversion to normal glucose tolerance was a roughly four-fold increase in the oral disposition index (from median 0·94 [IQR 0·68-1·35] at baseline to 3·90 [2·58-6·08] at follow-up; p<0·0001) and a significantly higher oral disposition index at follow-up compared with participants who maintained normal glucose tolerance across the study period (median 3·90 [IQR 2·58-6·08] vs 1·59 [1·12-2·23]; p<0·0001). By contrast, a decrease in insulin secretion was seen in participants who had persistent impaired glucose tolerance (median 1·31 [IQR 1·01-1·85]; p<0·0001) or who progressed to type 2 diabetes (0·20 [0·12-0·58]; p<0·0001), compared with participants who maintained normal glucose tolerance across the study period. Non-Hispanic white ethnic origin conferred five times the odds of reversion to normal glucose tolerance compared with non-Hispanic black ethnic origin (OR 5·06, 95% CI 1·86-13·76; p=0·001), with a two times greater annual increase in the oral disposition index (? 2·32, 95% CI 0·05-4·60; p=0·045). INTERPRETATION:Impaired glucose tolerance is highly reversible in obese adolescents. Ethnic origin is the main clinical modifier of the dynamic ?-cell response to prediabetic hyperglycaemia and, thus, determines the reversibility of impaired glucose tolerance, or its persistence. Therapeutic interventions for impaired glucose tolerance should target the specific mechanisms underpinning glucose tolerance changes in high-risk ethnic groups. FUNDING:National Institutes of Health (National Institute of Child Health and Human Development, National Center for Research Resources, and National Institute of Diabetes and Digestive and Kidney Diseases), American Diabetes Association, International Society for Pediatric and Adolescent Diabetes, Robert Leet Patterson and Clara Guthrie Patterson Trust, European Society for Pediatric Endocrinology, American Heart Association, and the Allen Foundation.
