Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic β-cells

Abstract

Diphosphoinositol pentakisphosphate (IP7) 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 Km for ATP of the IP7-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 IP7 concentration in β-cells. RNAi mediated knock down of the IP6K1 isoform inhibits both glucose-mediated increase in IP7 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 IP7 generation and insulin release. Thus the unique metabolic sensing properties of IP6K1 guarantees appropriate concentrations of IP7 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 IP7 generation may be an essential convergence point integrating multiple metabolic defects into the commonly observed phenotype in diabetes.

The Key Role of IP6K: A Novel Target for Anticancer Treatments?

“…The high turnover of PP-IPs shows significant ATP-dependent fluctuations, which operate as an energy-monitoring rheostat [ 43 ]. It has therefore been hypothesized that IP 7 can act as a “metabolic messenger” to coordinate energy flux and signaling pathways, as long as its biosynthesis depends on availability of ATP [ 19 , 44 ].…”

“…Finally, it is even more likely that the effects of IP 6 K1 on insulin are a secondary epiphenomenon, while ATP/ADP fluctuations are preferentially the master regulator of IP 7 release, as mentioned above [ 43 ]. Furthermore, it would be worthwhile investigating the relationships between IP 6 K1/IP 7 and mitochondrial activity.…”

Role of Inositols and Inositol Phosphates in Energy Metabolism

“…This particular orientation may be advantageous for electrostatic interaction with protein domains [29]. IP6K1 is known to be a crucial enzyme affecting alterations of metabolism and metabolic diseases which were studied by genetic deletion experiments [20][21][22]. Inositol pyrophosphates generated from IP6 have been shown to increase cellular energetics by increasing glycolysis and mitochondrial function [23].…”

Metabolism and Functions of Inositol Pyrophosphates: Insights Gained from the Application of Synthetic Analogues

“…In this context, it is notable that 5-InsP 7 levels fluctuate in response to the bioenergetic status of the cell (i.e., ATP levels) [ 56 ]; this homeostatic process underlies the role of 5-InsP 7 in mediating nutrient-stimulation of insulin secretion from pancreatic β-cells [ 56 ]. These observations rationalize 5-InsP 7 as being a rheostatic signaling molecule that protects bioenergetic health in the face of environmental challenges [ 1 , 6 ].…”