Open Access System for Information Sharing

Login Library

 

Article
Cited 0 time in webofscience Cited 0 time in scopus
Metadata Downloads

Inositol pyrophosphates and Akt: Is the pancreatic β-cell the exception to the rule?

Title
Inositol pyrophosphates and Akt: Is the pancreatic β-cell the exception to the rule?
Authors
RYU, SUNG HO
Date Issued
Jun-2019
Publisher
ELSEVIER SCIENCE INC
Abstract
The inositol pyrophosphate, diphosphoinositol pentakisphosphate (IP7), is thought to negatively regulate the critical insulin signaling protein Akt/PKB. Knock down of the IP7-generating inositol hexakisphosphate kinase 1 (IP6K1) results in a concomitant increase in signaling through Akt/PKB in all cell types so far examined. Total in vivo knockout of IP6K1 is associated with a phenotype resistant to high-fat diet, due to enhanced Akt/PKB signaling in classic insulin regulated tissues, counteracting insulin resistance. In contrast, we have shown an important positive role for IP6K1 in insulin exocytosis in the pancreatic β-cell. These cells also possess functional insulin receptors and the feedback loop following insulin secretion is a key aspect of their normal function. Thus we examined the effect of silencing IP6K1 on the activation of Akt/PKB in β-cells. Silencing reduced the glucose-stimulated increase in Akt/PKB phosphorylation on T308 and S473. These effects were reproduced with the selective pan-IP6K inhibitor TNP. The likely explanation for IP7 reduction decreasing rather than increasing Akt/PKB phosphorylation is that IP7 is responsible for generating the insulin signal, which is the main source of Akt/PKB activation. In agreement, insulin receptor activation was compromised in TNP treated cells. To test whether the mechanism of IP7 inhibition of Akt/PKB still exists in β-cells, we treated them at basal glucose with an insulin concentration equivalent to that reached during glucose stimulation. TNP potentiated the Akt/PKB phosphorylation of T308 induced by exogenous insulin. Thus, the IP7 regulation of β-cell Akt/PKB is determined by two opposing forces, direct inhibition of Akt/PKB versus indirect stimulation via secreted insulin. The latter mechanism is dominant, masking the inhibitory effect. Consequently, pharmacological strategies to knock down IP6K activity might not have the same positive output in the β-cell as in other insulin regulated tissues.
URI
http://oasis.postech.ac.kr/handle/2014.oak/95238
ISSN
0898-6568
Article Type
Article
Citation
CELLULAR SIGNALLING, vol. 58, page. 131 - 136, 2019-06
Files in This Item:
There are no files associated with this item.

qr_code

  • mendeley

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Related Researcher

Researcher

 RYU, SUNG HO
Dept of Life Sciences
Read more

Views & Downloads

Browse