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Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic β-cells.
- Source :
-
Cellular Signalling . Jun2018, Vol. 46, p120-128. 9p. - Publication Year :
- 2018
-
Abstract
- Diphosphoinositol pentakisphosphate (IP 7 ) is critical for the exocytotic capacity of the pancreatic β-cell, but its regulation by the primary instigator of β-cell exocytosis, glucose, is unknown. The high K m for ATP of the IP 7 -generating enzymes, the inositol hexakisphosphate kinases (IP6K1 and 2) suggests that these enzymes might serve as metabolic sensors in insulin secreting β-cells and act as translators of disrupted metabolism in diabetes. We investigated this hypothesis and now show that glucose stimulation, which increases the ATP/ADP ratio, leads to an early rise in IP 7 concentration in β-cells. RNAi mediated knock down of the IP6K1 isoform inhibits both glucose-mediated increase in IP 7 and first phase insulin secretion, demonstrating that IP6K1 integrates glucose metabolism and insulin exocytosis. In diabetic mouse islets the deranged ATP/ADP levels under both basal and glucose-stimulated conditions are mirrored in both disrupted IP 7 generation and insulin release. Thus the unique metabolic sensing properties of IP6K1 guarantees appropriate concentrations of IP 7 and thereby both correct basal insulin secretion and intact first phase insulin release. In addition, our data suggest that a specific cell signaling defect, namely, inappropriate IP 7 generation may be an essential convergence point integrating multiple metabolic defects into the commonly observed phenotype in diabetes. [ABSTRACT FROM AUTHOR]
- Subjects :
- *INSULIN
*EXOCYTOSIS
*GENE expression
*GLUCOSE
*DIABETES
Subjects
Details
- Language :
- English
- ISSN :
- 08986568
- Volume :
- 46
- Database :
- Academic Search Index
- Journal :
- Cellular Signalling
- Publication Type :
- Academic Journal
- Accession number :
- 128803961
- Full Text :
- https://doi.org/10.1016/j.cellsig.2018.03.001