Metabolic Markers Associated with Increased Risk for Progression from Single to Multiple Autoantibodies in Type 1 Diabetes Relatives

Abstract

Stage 1, defined as having ≥2 (i.e., multiple) autoantibodies (MA+) with normoglycemia, is currently identified as the earliest pathogenetic phase of type 1 diabetes. There is limited information of a possible β-cell function decline during the preceding phase, defined as single autoantibody positivity (SA+). Therefore, we evaluated metabolic measures at time of SA+ determination and assessed their predictive value for progression to MA+. Relatives participating in the TrialNet prospective Pathway to Prevention with SA+ (GADA, IAA, or IA-2A) were studied. Time from SA+ to MA+ was analyzed to assess risk of conversion. Measures evaluated during OGTT included: mean AUC for C-peptide, glucose, and insulin; fasting glucose and C-peptide; early insulin and C-peptide responses (30-0 min); peak C-peptide; glucose and C-peptide sums (30 to 120 min) and Index60 (incorporating fasting C-peptide, 1-hour glucose, and 1-hour C-peptide). Clinical factors included age, sex, ethnicity and autoantibody type. Of the 2,265 subjects identified as SA+, 57% were female, 83% white, 14% hispanic, with a median age of 14.8 years (range: 1.0 to 48.7 years). Most (71%) had GADA, 25% IAA and 4% IA-2A; 68% were tested also for ZnT8A. Overall, 407 (18%) SA+ progressed to MA+ during a median follow-up of 1.8 years. Adjusting for age, sex, and ethnicity we found that higher levels of mean AUC glucose (HR=2.4, p=0.004) significantly increased risk of progression to MA+. Index60 was significant both continuous (HR=1.17, p=0.004) and dichotomized (≥1 vs. <1; HR=2.28, p<0.0001). Reduced early C-peptide response was also significantly predictive (HR=0.94, p=0.007). Overall, we found that in early phase of SA+ there are already metabolic markers of beta cell dysfunction associated with increased risk of progression to MA+. These findings provide insights into early phases of the disease and provide the rationale for interventions at this stage. Disclosure E. Bosi: Consultant; Self; Abbott, AstraZeneca, Lexicon Pharmaceuticals, Inc., LifeScan, Inc.. Employee; Spouse/Partner; LifeScan, Inc.. Consultant; Self; Medtronic, Merck Sharp & Dohme Corp., Novartis AG, Roche Diabetes Care Health and Digital Solutions, Sanofi. S. Geyer: None. J. Sosenko: None. D.J. Becker: None. M. Battaglia: None. H.M. Ismail: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. L.H. Philipson: Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Merck & Co., Inc.. Research Support; Self; JAEB Center For Health Research, JDRF, Janssen Pharmaceuticals, Inc., Medtronic MiniMed, Inc.. J.P. Palmer: None. C. Evans-Molina: None.