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

• Published in: Cellular signalling Vol. 46; pp. 120 - 128
• Main Authors: Rajasekaran, Subu Surendran, Kim, Jaeyoon, Gaboardi, Gian-Carlo, Gromada, Jesper, Shears, Stephen B., dos Santos, Karen Tiago, Nolasco, Eduardo Lima, Ferreira, Sabrina de Souza, Illies, Christopher, Köhler, Martin, Gu, Chunfang, Ryu, Sung Ho, Martins, Joilson O., Darè, Elisabetta, Barker, Christopher J., Berggren, Per-Olof
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.06.2018; Elsevier Science Ltd
• Subjects: Adenosine Diphosphate - metabolism; Adenosine Triphosphate - metabolism; Animals; ATP/ADP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2 - metabolism; Diphosphoinositol pentakisphosphate/ IP7; Gene Knockdown Techniques; Glucose - metabolism; Humans; Inositol hexakisphosphate kinase 1; Inositol Phosphates - metabolism; Inositol Phosphates - physiology; Insulin Secretion; Insulin-Secreting Cells - enzymology; Insulin-Secreting Cells - metabolism; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Pancreatic beta cell; Phosphotransferases (Phosphate Group Acceptor) - genetics; Phosphotransferases (Phosphate Group Acceptor) - metabolism; Type 2 diabetes; Type 2 diabetes; IP7; Inositol hexakisphosphate kinase 1; ATP/ADP; T2D; Pancreatic beta cell; Diphosphoinositol pentakisphosphate/ IP7; IP6K; Insulin secretion; Diphosphoinositol pentakisphosphate/ IP
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2018.03.001

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. [Display omitted] •Glucose increases IP7 levels transiently through IP6K1 in pancreatic β-cells.•IP6K1 decodes glucose-driven increases in ATP/ADP ratio into 1st phase insulin release.•IP7 production and insulin release mirror perturbed metabolism in diabetic islets.•IP6K1 acts as a β-cell metabolic sensor under normal and pathological conditions.