Glucose modulation of insulin mRNA levels is dependent on transcription factor PDX-1 and occurs independently of changes in intracellular Ca2+

Wendy M. Macfarlane, Ruth M. Shepherd, Karen E. Cosgrove, Roger F L James, Mark J. Dunne, Kevin Docherty

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Glucose regulates insulin production in pancreatic β-cells in the long term by stimulating insulin gene transcription. These effects are partially mediated through the activity of a homeodomain transcription factor, PDX-1, which binds to four sites within the human insulin gene promoter. The availability of a human β-like cell line, NES2Y, which lacks PDX-1 but expresses the insulin gene, allowed us to determine whether PDX-1 was essential for the stimulatory effect of glucose on insulin mRNA levels. In NES2Y cells, glucose had no effect on the insulin gene promoter linked to a firefly luciferase reporter or on endogenous insulin mRNA levels. However, in NES2Y cells stably transfected with PDX-1 (NES-PDX-1), glucose exhibited a marked stimulatory effect on both the insulin promoter (5 ± 0.2-fold, n = 6) and insulin mRNA levels (4.8 ± 0.5-fold, n = 4). NES2Y cells were derived from a patient with persistent hyperinsulinemic hypoglycemia of infancy; the cells therefore lacked operational ATP-sensitive potassium channels, which results in the failure to control depolarization-dependent intracellular Ca2+ signaling. Despite the loss of control of Ca2+ channel activity, NES-PDX-1 cells maintained normal glucose-responsive insulin gene regulation. These results demonstrate that glucose modulation of insulin mRNA levels is dependent on the activity of PDX-1 and that these effects are independent of changes in intracellular Ca2+ concentrations.
    Original languageEnglish
    Pages (from-to)418-423
    Number of pages5
    JournalDiabetes
    Volume49
    Issue number3
    DOIs
    Publication statusPublished - Mar 2000

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