Insulin-Like Growth-Factor Axis Collectively Identifies Pre–Type 1 Diabetes

Abstract

Autoantibodies (AAb) against beta cell antigens are useful biomarkers for type 1 diabetes (T1D) prediction; however, staging of pre-T1D requires lengthy and invasive glucose tolerance testing. A need exists for additional serum biomarkers reflective of metabolic and immunologic dysregulation to test concurrently with AAb. The insulin-like growth factor (IGF) family, consisting of IGF1 and IGF2, has been shown to promote insulin action and possess immunoregulatory properties. Their activity is regulated by at least seven IGF binding proteins (IGFBPs). We hypothesized that IGF1 and IGF2 levels or bioavailability are reduced during T1D development. Total serum IGF1, IGF2, and IGFBP1-7 levels were measured in an age-matched (12.0 ± 3.7 years), cross-sectional cohort of AAb negative (AAb-) controls (CTRL) (n=74); AAb- first-degree relatives (AAb- FDR, n=55); FDR positive (AAb+ FDR) for one (n=23) or multiple (n=26) of GAD65, IA-2, or ZnT8 AAbs; new onset (NO) T1D patients (n=63, duration 1.0 ± 0.7 months); and established T1D patients (n=68, duration 4.4 ± 3.7 years). IGF1 and IGF2 levels were significantly lower in AAb+ FDR compared to AAb- FDR (204 ± 117 vs. 346 ± 160 ng/mL, p<0.001; 701 ± 496 vs. 1054 ± 721 ng/mL, p<0.01). Lower IGF1 levels were noted in single AAb+ FDR (183 ± 112 ng/mL, p<0.0001), while lower IGF2 levels remained significant in multiple AAb+ FDR only (686 ± 535 ng/mL, p<0.05). IGFBP1 levels were increased in AAb+ FDR compared to AAb- FDR (3.6 ± 3.2 vs. 1.8 ± 1.7 ng/mL, p<0.01), and this was apparent in single AAb+ FDR (4.5 ± 4.0 ng/mL, p<0.001). IGFBP7 levels were significantly lower in multiple AAb+ FDR as compared to AAb- FDR (79 ± 21 vs. 95 ± 22 ng/mL, p<0.05). Additionally, we established a multiple logistic regression model evaluating age, IGFs, and IGFBPs (IGFBP1, -3, and -7), which could effectively discriminate AAb+ FDR from CTRL (AUC = 0.84). These data suggest a dysregulated IGF axis is present prior to symptomatic T1D and may provide new biomarkers to improve disease prediction. Disclosure M. Shapiro: None. C. Wasserfall: None. A.R. Schultz: None. S.M. McGrail: None. M.J. Haller: None. D. Schatz: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. T.M. Brusko: Stock/Shareholder; Self; OneVax, LLC. Advisory Panel; Self; Caladrius Biosciences, Inc.. Consultant; Self; Merck & Co., Inc., Sanofi-Aventis.