Rapid Deterioration of Insulin Secretion in Obese Adolescents Preceding the Onset of Type 2 Diabetes

• Published in: The Journal of pediatrics Vol. 166; no. 3; pp. 672 - 678
• Main Authors: Elder, Deborah A., MD, Hornung, Lindsey N., MS, Herbers, Patricia M., MS, Prigeon, Ron, MD, Woo, Jessica G., PhD, D'Alessio, David A., MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2015
• Subjects: Adolescent; Blood Glucose - metabolism; Child; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - etiology; Female; Follow-Up Studies; Glucose Intolerance - blood; Glucose Intolerance - complications; Glycated Hemoglobin A - metabolism; Humans; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells - metabolism; Male; Pediatric Obesity - blood; Pediatric Obesity - complications; Pediatrics; Time Factors; Proinsulin; Type 2 diabetes; Oral glucose tolerance test; T2DM; Normal glucose tolerance; DI; Diabetes mellitus; AIR g; Proinsulin to insulin ratio; DM; Homeostatic model assessment of insulin resistance; Homeostatic model assessment; Acute insulin response to glucose; Body mass index; HOMA-IR; HbA 1c; Hemoglobin A1c; PI/I; PI; HOMA; NGT; Disposition index; OGTT; BMI; AIRg; HbA1c
• ISSN: 0022-3476; 1097-6833
• DOI: 10.1016/j.jpeds.2014.11.029

Objective To identify pathophysiologic changes that lead to the onset of type 2 diabetes (T2DM) in adolescents. Study design Obese adolescents with normal glucose tolerance (n = 41) were studied longitudinally over the course of 4 years with serial measure of the acute insulin response to glucose (AIRg ) as well as proinsulin (PI) concentrations. Insulin resistance was estimated with the homeostatic model assessment of insulin resistance (HOMA-IR), the disposition index (DI) computed as AIRg  × 1/HOMA-IR, and intravenous glucose tolerance estimated as the glucose disappearance constant. Results Four adolescents developed diabetes mellitus (DM) during the study, and the rest of the cohort remained nondiabetic. Baseline PI exceeded the IQR of the nondiabetic group in 3 of 4 subjects with DM, and all had >85% reduction from baseline AIRg , and DI, within 6 months of diagnosis. All the subjects with DM gained weight over the course of the study, but these changes paralleled those for the nondiabetic group. HOMA-IR increased substantially in 1 of the subjects with DM at the time of diagnosis but was comparable with baseline in the other 3. The DI and glucose disappearance constant of the subjects with DM was less than the 10th percentile of the nondiabetic group before and after diagnosis. Conclusion Conversion from normal glucose tolerance to T2DM in adolescents can occur rapidly, and the onset of T2DM is heralded by a substantial decrease in AIRg and DI, as well as increased release of PI. These results support loss of β-cell function as the proximate step in the development of T2DM in this age group.