Insulin-feedback via PI3K-C2α activated PKBα/Akt1 is required for glucose-stimulated insulin secretion

Barbara Leibiger, Tilo Moede, Sabine Uhles, Christopher J. Barker, Marion Creveaux, Jan Domin, Per Olof Berggren, Ingo B. Leibiger

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Phosphatidylinositide 3-kinases (PI3Ks) play central roles in insulin signal transduction. While the contribution of class Ia PI3K members has been extensively studied, the role of class II members remains poorly understood. The diverse actions of class II PI3K-C2α have been attributed to its lipid product PI(3)P. By applying pharmacological inhibitors, transient overexpression and small-interfering RNA-based knockdown of PI3K and PKB/Akt isoforms, together with PI-lipid profiling and live-cell confocal and total internal reflection fluorescence microscopy, we now demonstrate that in response to insulin, PI3K-C2α generates PI(3,4)P2, which allows the selective activation of PKBα/Akt1. Knockdown of PI3K-C2α expression and subsequent reduction of PKBα/Akt1 activity in the pancreatic β-cell impaired glucose-stimulated insulin release, at least in part, due to reduced glucokinase expression and increased AS160 activity. Hence, our results identify signal transduction via PI3K-C2α as a novel pathway whereby insulin activates PKB/Akt and thus discloses PI3K-C2α as a potential drugable target in type 2 diabetes. The high degree of codistribution of PI3K-C2α and PKBα/Akt1 with insulin receptor B type, but not A type, in the same plasma membrane microdomains lends further support to the concept that selectivity in insulin signaling is achieved by the spatial segregation of signaling events.

Original languageEnglish (US)
Pages (from-to)1824-1837
Number of pages14
JournalFASEB Journal
Volume24
Issue number6
DOIs
StatePublished - Jun 1 2010

Keywords

  • Biosensors
  • Diabetes mellitus
  • Fluorescence microscopy
  • Insulin signaling

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

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    Leibiger, B., Moede, T., Uhles, S., Barker, C. J., Creveaux, M., Domin, J., Berggren, P. O., & Leibiger, I. B. (2010). Insulin-feedback via PI3K-C2α activated PKBα/Akt1 is required for glucose-stimulated insulin secretion. FASEB Journal, 24(6), 1824-1837. https://doi.org/10.1096/fj.09-148072