| Autor: |
Macfarlane, Wendy M., Shepherd, Ruth M., Cosgrove, Karen E., James, Roger F.L., Dunne, Mark J., Docherty, Kevin, Macfarlane, W M, Shepherd, R M, Cosgrove, K E, James, R F, Dunne, M J, Docherty, K |
| Předmět: |
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| Zdroj: |
Diabetes; Mar2000, Vol. 49 Issue 3, p418-423, 6p, 1 Black and White Photograph, 4 Graphs |
| Abstrakt: |
Glucose regulates insulin production in pancreatic beta-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 beta-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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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