2154-LB: Rapid Appearance of Newly Synthesized Insulin and C-Peptide in Plasma (Reduced Residence Time in β-Cells) Is a Noninvasive Measure of Loss of Insulin Reserve in ZDF Rats

Introduction and Objective: T2D evolves through progressive loss of β-cell secretory capacity and insulin reserve. Non-invasive detection of insulin depletion in β-cells has not been possible. We tested a flux-based method for identifying reduced β-cell insulin stores non-invasively. The time for newly synthesized Ins and C-P to appear and become fully labeled in plasma reveals residence time (RT) in β-cells. We hypothesized that depleted insulin reserves results in new Ins and C-P passing through β-cells and appearing in plasma more rapidly (shorter RT). Methods: Female ZDF rats (n=24/group) were fed chow or high fat diet, the latter to induce T2D. 2H2 O was given for 1-48 hr, with high-resolution mass spectrometry of plasma Ins and C-P deuterium labeling patterns over time of 2H2 O exposure Results: Fractional synthesis rate (FSR) of Ins was significantly faster and RT (1.0/FSR) was shorter (A, RT 2.3 vs. 5.4 hr, p<0.0001) in T2D. RT of C-P also was shorter (B, 2.5 vs. 5.9 hr, p<0.0001) in T2D and correlated closely with Ins RT. plasma Ins or C-P RT measured at 3 or 6 hr differentiated all T2D from non-T2D rats (p<0.001). Other markers were consistent with β-cell failure. Conclusion: RT of Ins or C-P measured in plasma is a non-invasive window into depletion of β-cell insulin. This non-invasive assay of β-cell loss of secretory reserve is translatable into humans. Disclosure M.K. Hellerstein: Research Support; Lilly USA LLC. Consultant; Lilly USA LLC. E.J. Zanley: None. J. Willency: Employee; Eli Lilly and Company. V. Pirro: Employee; Eli Lilly and Company. O. Cabrera: Employee; Eli Lilly and Company. Funding Lilly LRAP