Phenotypes Associated With Zones Defined by Area Under the Curve Glucose and C-peptide in a Population With Islet Autoantibodies

OBJECTIVEMetabolic zones were developed to characterize heterogeneity of individuals with islet autoantibodies. RESEARCH DESIGN AND METHODSBaseline 2-h oral glucose tolerance test 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 five area under the curve glucose (AUCGLU) rows and five area under the curve C-peptide (AUCPEP) columns. Zone phenotypes were developed from demographic, metabolic, autoantibody, HLA, and risk data. RESULTSAs AUCGLU increased, changes of glucose and C-peptide response curves (from mean glucose and mean C-peptide values at 30, 60, 90, and 120 min) were similar within the five AUCPEP columns. Among the zones, 5-year risk for type 1 diabetes was highly correlated with islet antigen 2 antibody prevalence (r = 0.96, P < 0.001). Disease risk decreased markedly in the highest AUCGLU row as AUCPEP increased (0.88-0.41; P < 0.001 from lowest AUCPEP column to highest AUCPEP column). AUCGLU correlated appreciably less with Index60 (an indicator of insulin secretion) in the highest AUCPEP column (r = 0.33) than in other columns (r & GE; 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). CONCLUSIONSPhenotypes of 25 zones formed from AUCGLU and AUCPEP were used to gain insights into type 1 diabetes heterogeneity. Zones were used 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.

Automated summary

Metabolic zones were formed based on AUCGLU and AUCPEP to explore the heterogeneity of type 1 diabetes. The zones were highly correlated with islet autoantibodies, and the predictive ability of glucose for risk depended on the level of C-peptide. Glucose secretion and insulin resistance made different contributions to glucose heterogeneity and diabetes risk.