1200-OR: HER2 Inhibition: A Strategy for Restoring Normoglycemia and Beta-Cell Maturity

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Introduction and Objective: Given the urgent clinical need to restore long term blood glucose control, this study has established efficacy of BI-1622, a Her2 inhibitor initially developed for therapy of Her2-associated cancer, for diabetes intervention in preclinical models and human islets. Methods: BI-1622 (10 mg/kg) or vehicle was i.p. injected for 4 weeks into db/db, multiple low dose streptozotocin C57Bl/6J wild-type and in normal diet and high fat/high sucrose (Surwit) fed mice (drug intervention after 10 weeks on diets for another 10 weeks). Human islets were treated with 1-10 microM BI-1622 and 22.2 mM glucose/0.5 mM palmitic acid (glucolipotoxicity) or coxsackieviruses (CVB3/CVB4) for 72 h; RT-PCR, western blotting, mmunocytochemistry and GSIS performed thereafter. Statistics was analysed by two-way Anova with Bonferroni’s multiple comparison. Results: Daily administration of BI-1622 ameliorated hyperglycemia, improved insulin secretion and promoted survival of highly functional and mature β-cells and prevented β-cell dedifferentiation in three mouse models of T2D and T1D. In human isolated islets, Her2i restored functional and mature β-cells, improved survival, protected from glucolipotoxicity and coxsackievirus induced inflammation. In organ donors with pre-diabetes and T2D, Her2i lowered inflammatory gene expression and stabilized β-cell function and maturation markers. Conclusion: As prior studies have suggested that EGFR/ErbB signaling supports β-cell growth and survival, the protective action of Her2 inhibition is unexpected. Our results suggest that under pro-diabetic, gluco-lipotoxic and pro-inflammatory conditions, Her2 becomes maladaptively activated, contributing to β-cell dysfunction, stress signaling, and loss of identity. Given the extensive clinical experience with Her2 inhibitors in oncology, repurposing them for β-cell-directed therapy could lead to rapid clinical translation of our study for patients with diabetes, both T1D and T2D, and especially for patients with severe cancer/diabetes comorbidity. Disclosure K. Maedler: None. A.C. Puhl: None. T. Klein: Employee; Current; Boehringer Ingelheim International GmbH.

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