Index60 Is More Strongly Associated with the Highest Type 1 Diabetes (T1D) Risk HLA DR3-DQ2/DR4-DQ8 (DQ2/DQ8) Genotype than Glucose Measures

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.