Diphosphoinositol pentakisphosphate as a novel mediator of insulin exocytosis

Christopher J. Barker, Christopher Illies, Roberta Fiume, Gian Carlo Gaboardi, Jia Yu, Per Olof Berggren

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


The pancreatic β-cell has served as an important model system for the revelation of new physiological roles for inositides. Initially, our studies were restricted to the role of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) in the regulation of cytoplasmic free calcium concentration ([Ca2+]i), but it soon became clear that other inositol phosphates could also regulate β-cell [Ca2+]i. For example, inositol hexakisphosphate (InsP6) promotes the opening of the key voltage-dependent L-type Ca2+ channels, responsible for Ca2+ influx and the final release of insulin. Furthermore, InsP6 and inositol lipids such as phosphatidylinositol 4,5-bisphosphate are intimately involved the regulation of endocytosis and exocytosis. We now review our most recent work, which has focused on the phosphorylation product of InsP6, diphosphoinositol pentakisphosphate (PP-InsP5 or InsP7). We have established that InsP7 via the activity of the InsP6 kinase, IP6K1, promotes insulin release from the readily releasable pool of vesicles (RRP). The RRP is thought to be synonymous with the first phase of insulin secretion. This has a direct implication for type 2 diabetes, as it is this initial phase of insulin release that is curtailed in the disease. Hints from human genetic linkage studies suggest that disruption of IP6K1 could be a factor in the development of type 2 diabetes and a recent mouse model, where IP6K1 is universally deleted, exhibits lowered plasma insulin levels. Hence, this is yet another important example demonstrating how the β-cell utilizes inositides in the regulation of function. Although we do not fully understand the underlying molecular mechanisms, it is clear that IP6K1-mediated production of InsP7 has an essential role in the regulation of the insulin secretory process.

Original languageEnglish (US)
Pages (from-to)168-173
Number of pages6
JournalAdvances in Enzyme Regulation
Issue number1
StatePublished - 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Cancer Research


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