American Diabetes Association
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Phenotypes Associated with Zones Defined by Area Under the Curve Glucose and C-peptide in a Population with Islet Autoantibodies

posted on 2023-03-31, 16:25 authored by Jay M. Sosenko, David Cuthbertson, Emily K. Sims, Heba M. Ismail, Brandon M. Nathan, Laura M. Jacobsen, Mark A. Atkinson, Carmella Evans-Molina, Kevan C. Herold, Jay S. Skyler, Maria J. Redondo, theTrialNet Study Group



Metabolic zones were developed to characterize heterogeneity of individuals with islet autoantibodies.

Research Design and Methods

Baseline 2-hour oral glucose tolerance test (OGTT) data from 6,620 TrialNet Pathway to Prevention Study (TNPTP) autoantibody-positive participants (relatives of individuals with type 1 diabetes) were used to form 25 zones from 5 AUC glucose (AUCGLU) rows and 5 AUC C-peptide (AUCPEP) columns. Zone phenotypes were developed from demographic, metabolic, autoantibody, HLA, and risk data.


As AUCGLU increased, changes of glucose and C-peptide response curves (GCRCs; from mean glucose and mean C-peptide values at 30,60,90,120 minutes) were similar within the 5 AUCPEP columns. Among the zones, 5-year risk for type 1 diabetes was highly correlated with IA-2A prevalence (r=0.96, p<0.001). Disease risk decreased markedly in the highest AUCGLU row as AUCPEP increased (0.88 to 0.41; p<0.001 from lowest AUCPEP to highest AUCPEP column). AUCGLU correlated appreciably less with Index60 (indicator of insulin secretion) in the highest AUCPEP column (r=0.33) than in other columns (r≥0.78). AUCGLU was positively related to “fasting glucose x fasting insulin” and to “fasting glucose x fasting C-peptide” (indicators of insulin resistance) before and after adjustments for Index60 (p<0.001). 


Phenotypes of 25 zones formed from AUCGLU and AUCPEP were used to gain insights into type 1 diabetes heterogeneity. Zones were utilized to examine GCRC changes with increasing AUCGLU, associations between risk and autoantibody prevalence, the dependence of glucose as a predictor of risk according to C-peptide, and glucose heterogeneity from contributions of insulin secretion and insulin resistance.