Mechanism and regulation of biotin uptake by mouse and human pancreatic beta cells/islets: physiological and molecular aspects (909.2)

Abstract

Biotin is essential for normal cellular function of all pancreatic cells. Little, however, is known about how pancreatic beta cells obtain biotin and the molecular identity of the system involved and its regulation. We addressed these issues using mouse‐derived beta‐TC‐6 cells as well as freshly isolated mouse and human primary pancreatic islets. Our results showed biotin uptake by beta‐TC‐6 cells is carrier‐mediated, Na‐dependent, cis‐inhibited by structural analogs and by pantothenic acid, and is saturable (apparent Km of 17 µM). Similarly, freshly isolated mouse and human primary pancreatic islets took in biotin via a carrier‐mediated Na‐dependent mechanism. These studies suggest the involvement of the Na‐dependent multivitamin transporter, SMVT; this was confirmed in studies using gene specific knockdown (shRNA) approach. Uptake of biotin was also adaptively‐regulated by extracellular vitamin levels through a transcriptional mechanism (s). Maintaining (96 hr) pancreatic beta cells in hyper‐glycemic condition (26 mM) did not affect biotin uptake. Exposer to specific cytokines (IL‐1β+TNF‐+IFN‐), whose level increases in diabetes, led to a significant inhibition in biotin uptake. The results show for the first time that biotin uptake by pancreatic beta cells is via a cytokine sensitive carrier‐mediated process that involves the SMVT system.Grant Funding Source: Supported by DVA and NIH (DK58057, AA‐18071 and DK56061