3042-LB: Residence Time (RT) of Insulin and C-Peptide Reveals Reversible vs. Treatment-Resistant ß-Cell Dysfunction in Female ZDF rats (fZDF) on High-Fat Diet (HFD)

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Introduction and Objective: β-cell secretory reserve declines prior to overt hyperglycemia but there are no direct clinical biomarkers. We asked whether shorter RT of insulin (Ins) or C-peptide (C-P) in β-cells before secretion non-invasively reveals reversibility of β-cell dysfunction in HFD-fed fZDF treated with rosiglitazone (Rosi). Methods: fZDF were on HFD or chow for 10, 20, or 40 days before 15d of Rosi or placebo, still on HFD. ²H2O was given 3h pre-sacrifice. RT was measured by high-resolution mass spectrometry of mass isotopomer enrichments in plasma and islet Ins1, Ins2, and C-P. Groups were compared by Tukey’s test. Results: Plasma glucose rose after 10d HFD and fell with Rosi treatment at d10 and d20, but not d40. fZDF on HFD vs chow had shorter Ins RT measured in plasma (Fig 1) at d10 (2.0 vs 4.2h), d20 (2.4 vs 4.0h) and d40 (2.1 vs 4.3h). Rosi at d10 or d20 prolonged Ins RT (4.9 and 5.9h) but not at d40 (2.2h). C-P results were similar. In islets, Rosi at d20 prolonged Ins RT (22 vs 8.4h), but not at d40 (16.9 vs 13.6h), consistent with glycemic, hormonal and β-cell markers of failure. RT in plasma was consistently shorter than in islets, especially in β-cell stress, revealing preferential secretion of newly synthesized Ins. Conclusion: Ins and C-P RT in this model of progressive β-cell failure, provide a non-invasive, translatable quantitative biomarker of reversible versus treatment-resistant β-cell dysfunction. Disclosure E. Zanley: None. J. Willency: Employee; Current; Eli Lilly and Company. Stock/Shareholder; Current; Eli Lilly and Company. J.V. Ficorilli: Employee; Current; Eli Lilly and Company. K.W. Li: None. O. Cabrera: Employee; Current; Eli Lilly and Company. M.K. Hellerstein: Research Support; Current; Lilly, Merck & Co., Inc.

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