HOMA2-B enhances assessment of type 1 diabetes risk among TrialNet Pathway to Prevention participants

Abstract

Aims/hypothesis: Methods to identify individuals at highest risk for type 1 diabetes are essential for the successful implementation of disease-modifying interventions. Simple metabolic measures are needed to help stratify autoantibody-positive (Aab+) individuals who are at risk of developing type 1 diabetes. HOMA2-B is a validated mathematical tool commonly used to estimate beta cell function in type 2 diabetes using fasting glucose and insulin. The utility of HOMA2-B in association with type 1 diabetes progression has not been tested.

Methods: Baseline HOMA2-B values from single-Aab+ (n = 2652; mean age, 21.1 ± 14.0 years) and multiple-Aab+ (n = 3794; mean age, 14.5 ± 11.2 years) individuals enrolled in the TrialNet Pathway to Prevention study were compared. Cox proportional hazard models were used to determine associations between HOMA2-B tertiles and time to progression to type 1 diabetes, with adjustments for age, sex, HLA status and BMI z score. Receiver operating characteristic (ROC) analysis was used to test the association of HOMA2-B with type 1 diabetes development in 1, 2, 5 and 10 years.

Results: At study entry, HOMA2-B values were higher in single- compared with multiple-Aab+ Pathway to Prevention participants (91.1 ± 44.5 vs 83.9 ± 38.9; p < 0.001). Single- and multiple-Aab+ individuals in the lowest HOMA2-B tertile had a higher risk and faster rate of progression to type 1 diabetes. For progression to type 1 diabetes within 1 year, area under the ROC curve (AUC-ROC) was 0.685, 0.666 and 0.680 for all Aab+, single-Aab+ and multiple-Aab+ individuals, respectively. When correlation between HOMA2-B and type 1 diabetes risk was assessed in combination with additional factors known to influence type 1 diabetes progression (insulin sensitivity, age and HLA status), AUC-ROC was highest for the single-Aab+ group's risk of progression at 2 years (AUC-ROC 0.723 [95% CI 0.652, 0.794]).

Conclusions/interpretation: These data suggest that HOMA2-B may have utility as a single-time-point measurement to stratify risk of type 1 diabetes development in Aab+ individuals.

Keywords: Autoantibody; Biomarker; HOMA2-B; Risk prediction; TrialNet Pathway to Prevention; Type 1 diabetes.

Fig. 1

CONsolidated Standards of Reporting Trials (CONSORT) diagram for Pathway to Prevention screening and confirmatory testing. Numbers of participants identified as of 31 May 2019 are indicated. First-, second- and third-degree relatives of individuals with type 1 diabetes were screened for the presence of islet autoantibodies. A total of 218,865 eligible individuals were screened. Aab+ participants were invited to participate in longitudinal monitoring. Multiple-Aab+ participants who had at least one OGTT and fasting TOSOH insulin (n=3794) were included in the final analysis cohort. Single-Aab+ participants received confirmatory testing, and those with confirmed Aab+ status and who had at least one OGTT and fasting TOSOH insulin (n=2652) were also included in the final analysis cohort. Type 1 diabetes developed in 4.4% and 26.9% of the single-Aab+ and multiple-Aab+ groups, respectively. Within the single-Aab+ group, 483 participants (18.2%) developed additional autoantibodies and remained classified as single-Aab+ participants. T1D, type 1 diabetes

Fig. 2

Diabetes-free survival by HOMA2-B tertile. Kaplan–Meier curves of diabetes-free survival by HOMA2-B tertile for single-Aab+ (a) and multiple-Aab+ (b) cohorts. Grey lines, bottom tertile; blue lines, middle tertile; red lines, top tertile. HOMA2-B ranges for the corresponding tertiles are indicated in parentheses. p values were determined by logrank test

Fig. 3

Lower HOMA2-B tertiles correlate with increased risk for type 1 diabetes. Cox proportional hazards regression analysis by autoantibody status for single-Aab+ (a) and multiple-Aab+ (b) cohorts with adjustment for age, sex, HLA status and BMI z score. The lowest HOMA2-B tertile corresponds with the highest type 1 diabetes development risk for single- and multiple-Aab+ cohorts. Grey lines, bottom tertile; blue lines, middle tertile; red lines, top tertile. HOMA2-B ranges for the corresponding tertiles are indicated in parentheses. p values were determined by logrank test

Fig. 4

Association of HOMA2-B with type 1 diabetes progression by autoantibody status. AUC-ROC for HOMA2-B by autoantibody status for combined single- and multiple-Aab+ (a), single-Aab+ (b) and multiple-Aab+ (c) participants to assess association with type 1 diabetes development at 1, 2, 5 and 10 years from study entry

Fig. 5

Association of HOMA2-B with type 1 diabetes progression by type 1 diabetes stage. AUC-ROC- for HOMA2-B to assess correlation with type 1 diabetes development at 1, 2, 5 and 10 years from study entry in participants with stage 1 type 1 diabetes (multiple-Aab+ and normal glucose tolerance) (a) and stage 2 type 1 diabetes (multiple-Aab+ and abnormal glucose tolerance) (b). Glucose tolerance was assessed by OGTT at study entry

Fig. 6

Multivariate analysis strengthens the correlation between HOMA2-B and type 1 diabetes progression. Multivariate logistic regression model, with HOMA2-S, HLA status and age (categorised), to assess the association of HOMA2-B with type 1 diabetes progression for all participants (a), single-Aab+ participants (b) and multiple-Aab+ participants (c)