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

Author(s):Show less -

Rajasekaran, Subu Surendran ^[1] ; Kim, Jaeyoon ^{[1, 2]} ; Gaboardi, Gian-Carlo ^[1] ; Gromada, Jesper ^[3] ; Shears, Stephen B. ^[4] ; dos Santos, Karen Tiago ^{[1, 5]} ; Nolasco, Eduardo Lima ^{[1, 5]} ; Ferreira, Sabrina de Souza ^{[1, 5]} ; Illies, Christopher ^[1] ; Kohler, Martin ^[1] ; Gu, Chunfang ^[4] ; Ryu, Sung Ho ^[6] ; Martins, Joilson O. ^[5] ; Dare, Elisabetta ^[1] ; Barker, Christopher J. ^[1] ; Berggren, Per-Olof ^{[1, 2]}

Affiliation

^[1] Karolinska Inst, Rolf Luft Res Ctr Diabet & Endocrinol, SE-17176 Stockholm - Sweden

^[2] Pohang Univ Sci & Technol, Sch Interdisciplinary Biosci & Bioengn, Pohang 37673, Gyeongbuk - South Korea

^[3] Regeneron Pharmaceut Inc, 777 Old Saw Mill River Rd, Tarrytown, NY 10591 - USA

^[4] NIEHS, Signal Transduct Lab, Inositol Signaling Grp, Bldg 101, Room F239, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 - USA

^[5] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, Lab Immunoendocrinol, Sao Paulo - Brazil

^[6] Pohang Univ Sci & Technol POSTECH, Dept Life Sci, Pohang 37673 - South Korea

• Document type: Journal article
• Source: CELLULAR SIGNALLING; v. 46, p. 120-128, JUN 2018.
• Web of Science Citations: 3

Abstract

Diphosphoinositol pentakisphosphate (IP7) is critical for the exocytotic capacity of the pancreatic beta-cell, but its regulation by the primary instigator of beta-cell exocytosis, glucose, is unknown. The high K-m 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 beta-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 beta-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. (AU)

• FAPESP's process: 14/05214-1 - Investigating the role of insulin in different infections in diabetic and healthy animals
• Grantee: Joilson de Oliveira Martins
• Support Opportunities: Regular Research Grants
• FAPESP's process: 10/02272-0 - Effect of insulin on lung inflammation in animal with sepsis, innate immunit,activation of insulin gene (BGK) and insulin receptors (IR)-A and IR-B
• Grantee: Joilson de Oliveira Martins
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 17/11540-7 - Investigating the role of insulin in the presence of allergic pulmonary inflammation in diabetic and healthy mice
• Grantee: Joilson de Oliveira Martins
• Support Opportunities: Regular Research Grants