Effect of the FGF1-B promoter on spontaneous beta-cell tumorigenesis in F1B-Tag mice: A robust translational model for insulinoma and metabolic crosstalk.

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Background: Fibroblast growth factor 1 (FGF1) is a key regulator of glucose homeostasis and β-cell physiology. The F1B-Tag transgenic mouse, utilizing the FGF1-B promoter to drive SV40 T-antigen expression, provides a unique opportunity to study spontaneous tumorigenesis. This study characterizes the F1B-Tag model as a clinically relevant platform for human insulinoma, focusing on the molecular interplay between the FGF1-B promoter and pancreatic β-cell transformation. Methods: F1B-Tag mice were monitored longitudinally to evaluate oncogenic progression. Immunohistochemical (IHC) analysis was performed to co-localize SV40 T-antigen with FGF1 and proliferation markers. Metabolic profiling included blood glucose monitoring, fasting insulin ELISA, and Glucose Tolerance Tests (GTT). Results: F1B-Tag mice developed spontaneous tumors, with pancreatic lesions appearing at approximately 5 months of age. Tumorigenesis was specifically localized to the insulin-secreting β-cells within the pancreatic islets, rather than the ductal cells. IHC confirmed that the FGF1-B promoter actively drives T-antigen expression within these cells, triggering uncontrolled proliferation. Progressed F1B-Tag mice exhibited a statistically significant and marked reduction in both random and fasting blood sugar levels compared to age-matched wild-type (WT) controls. This hypoglycemic state was driven by profound hyperinsulinemia, where fasting plasma insulin levels in F1B-Tag mice were substantially and significantly elevated, reaching nearly twenty-fold higher than WT levels after normalization. GTT revealed a persistent, flattened low-glucose response curve following glucose administration, confirming autonomous and pathological insulin over-secretion. Conclusions: The F1B-Tag mouse is a robust translational model that accurately recapitulates the metabolic disturbances and oncogenic progression of insulinoma. Our findings demonstrate that the FGF1-B promoter is a critical driver in β-cell oncogenesis and glucose-sensing circuits. This model offers a valuable therapeutic screening platform for investigating novel FGF1-targeted therapies and modulating tumor-induced metabolic dysfunction.