Diphosphoinositol pentakisphosphate as a novel mediator of insulin exocytosis.

Inositides are key cellular regulators, but their role in physiology has often lagged behind our understanding of their biochemical and metabolic interactions ( [Irvine and Schell, 2001], [Seeds et al., 2007] and [Shears, 2004]). The pancreatic β-cell has provided a key physiological and pathophysiological platform for several important advances in our understanding of inositide-mediated cellular regulation ( [Barker et al., 2002] and [Berggren and Barker, 2008]). This is because the main purpose of the β-cell is the control of glucose homeostasis, by the regulated release of insulin. Thus impairment of β-cell function in man leads to the development of type 2 diabetes (Guillausseau et al., 2008). Our work has revealed that inositides are key players at all levels of the β-cell stimulus-secretion coupling process (Berggren and Barker, 2008). This includes the regulation of cytoplasmic free Ca2+ concentration, [Ca2+]i, both by inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-sensitive stores and the inositol hexakisphosphate(InsP6)-dependent gating of Ca2+ through voltage-gated L-type Ca2+-channels ( [Larsson et al., 1997] and [Barker et al., 2002]). A new area of inositide research that has been given much attention in the last few years is the study of the pyrophosphate derivatives of both inositol 1,3,4,5,6-pentakisphosphate (InsP5) and InsP6 ( [Bennett et al., 2006], [Shears, 2007], [Majerus, 2007] and [York and Lew, 2008]). Again, it seems that the pancreatic β-cell has an important role in shaping our thinking about how these pyrophosphates act within a physiological and possibly a pathophysiological milieu.