67-OR: Oral Minimal Model Testing Reveals Early Impairment of Insulin Sensitivity in Type 1 Diabetes Autoantibody Positive, Nonobese, Nondysglycemic Youth

Background: Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a pre-symptomatic phase characterized by multiple islet autoimmunity with normal glucose tolerance (Stage 1 T1D), followed by dysglycemia (Stage 2). The metabolic phenotypes of beta-cell function and insulin sensitivity were explored in normoglycemic youth with stage 1 T1D and compared to healthy non-related peers during a 3-h oral glucose tolerance test (OGTT). Methods: Participants were recruited from TrialNet (cases) and Yale University (controls). Twenty-eight lean youth with at least two islet autoantibody (cases) and 32 healthy controls underwent a 3-hour 9-point OGTT with measurement of glucose, C-peptide and insulin. The oral minimal model was used to quantitate beta-cell responsivity (Phitotal) and insulin sensitivity (SI), allowing assessment of beta-cell function by the disposition index, DI=Phitotal x SI. Subjects with impaired fasting glucose, impaired glucose tolerance or any OGTT glucose concentration >200mg/dL were excluded. Results: Cases (10.5y[8, 15]) exhibited reduced DI (p Conclusion: Pre-symptomatic stage 1 T1D is associated with both reduced insulin sensitivity and lower beta cell responsiveness in youth. Disclosure A. Galderisi: None. A. Moran: Advisory Panel; Self; Dompe, Novo Nordisk, Research Support; Self; Abbott Diabetes, Intrexon, Provention Bio, Inc. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc. M. Martino: None. N. Santoro: None. S. Caprio: None. C. Cobelli: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD40787, R01DK111038, R01HD28016, R01DK114504); National Center for Research Resources (UL1RR0249139); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK111038); Diabetes Research Center (P30DK045735, R01DK114504-01A, K12AWDA10768, GR103182); National Institutes of Health (U01DK085476, UL1TR002494, U01DK085505); Fondazione Cassa di Risparmio di Padova e Rovigo (2018); European Commission (EU951933)