Dysglycemia (i.e., fasting glucose=110-125 mg/dl; 30, 60, or 90-minutes glucose ≥200 mg/dl; and/or 2-h glucose=140-199 mg/dl, from oral glucose tolerance test [OGTT]) is used both as a predictive marker and pre-diagnostic endpoint in T1D prevention trials. However, recent evidence suggests that Index60 (based on fasting C-peptide, 60-minutes glucose and 60-minutes C-peptide, from OGTT) at a 1.00 threshold may be superior to dysglycemia. We thus hypothesized that Index60 is more strongly associated with T1D-linked genetic factors than glucose measures alone. We compared autoantibody-positive TrialNet Pathway to Prevention Study participants (n=1,098) with or without DQ2/DQ8 for associations with Index60, fasting glucose, 2-h glucose and dysglycemia. Participants with DQ2/DQ8 (n=159) compared to those without it (n=912) had higher Index60 values (median [interquartile range, IQR]=0.6 [-5.6 to 2.6] vs. 0.25 (-4.4 to 2.9]; p=0.001). In contrast, neither fasting glucose (p=0.51) nor 2-hour glucose p=0.07) were significantly different between the groups. The percentage with Index60≥1.00 was significantly higher in participants with (37.6%) than without (22.8%) DQ2/DQ8 (p=0.0001), whereas the percentages with dysglycemia were not significantly different (32.7% vs. 26.1%; p=0.11). Among those with normal OGTTs, Index60≥1.00 was more frequent among participants with DQ2/DQ8 (23.8%) than without it (12.0%; p=0.001), while among participants with Index60<1.00, the frequency of dysglycemia was similar in those with and without DQ2/DQ8 (17.5% vs. 16.0%; p=0.70).
In conclusion, Index60, a metabolic marker based on glucose and C-peptide, is more strongly associated with the highest T1D risk HLA DQ2/DQ8 genotype than glucose measures, including dysglycemia. This suggests that Index60 has higher pathogenic specificity for T1D than glucose measures and should be considered for use in T1D prevention trials.
M.J. Redondo: None. S. Geyer: None. H.M. Ismail: None. K.C. Herold: None. A. Pugliese: None. J.P. Palmer: None. J. Sosenko: None.