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 Citations (Scopus)

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

Fingerprint

Phosphotransferases
Insulin
Feedback
Glucose
Signal transduction
Signal Transduction
Membrane Microdomains
Lipids
Glucokinase
Fluorescence microscopy
Insulin Receptor
Cell membranes
Medical problems
Fluorescence Microscopy
Type 2 Diabetes Mellitus
Small Interfering RNA
Protein Isoforms
Chemical activation
Cell Membrane
Pharmacology

Keywords

  • Biosensors
  • Diabetes mellitus
  • Fluorescence microscopy
  • Insulin signaling

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Leibiger, B., Moede, T., Uhles, S., Barker, C. J., Creveaux, M., Domin, J., ... 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

Insulin-feedback via PI3K-C2α activated PKBα/Akt1 is required for glucose-stimulated insulin secretion. / Leibiger, Barbara; Moede, Tilo; Uhles, Sabine; Barker, Christopher J.; Creveaux, Marion; Domin, Jan; Berggren, Per Olof; Leibiger, Ingo B.

In: FASEB Journal, Vol. 24, No. 6, 01.06.2010, p. 1824-1837.

Research output: Contribution to journalArticle

Leibiger, B, Moede, T, Uhles, S, Barker, CJ, Creveaux, M, Domin, J, Berggren, PO & Leibiger, IB 2010, 'Insulin-feedback via PI3K-C2α activated PKBα/Akt1 is required for glucose-stimulated insulin secretion', FASEB Journal, vol. 24, no. 6, pp. 1824-1837. https://doi.org/10.1096/fj.09-148072
Leibiger, Barbara ; Moede, Tilo ; Uhles, Sabine ; Barker, Christopher J. ; Creveaux, Marion ; Domin, Jan ; Berggren, Per Olof ; Leibiger, Ingo B. / Insulin-feedback via PI3K-C2α activated PKBα/Akt1 is required for glucose-stimulated insulin secretion. In: FASEB Journal. 2010 ; Vol. 24, No. 6. pp. 1824-1837.
@article{82c6a5566e9b45c6bac57cd6c0694998,
title = "Insulin-feedback via PI3K-C2α activated PKBα/Akt1 is required for glucose-stimulated insulin secretion",
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.",
keywords = "Biosensors, Diabetes mellitus, Fluorescence microscopy, Insulin signaling",
author = "Barbara Leibiger and Tilo Moede and Sabine Uhles and Barker, {Christopher J.} and Marion Creveaux and Jan Domin and Berggren, {Per Olof} and Leibiger, {Ingo B.}",
year = "2010",
month = "6",
day = "1",
doi = "10.1096/fj.09-148072",
language = "English",
volume = "24",
pages = "1824--1837",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "6",

}

TY - JOUR

T1 - Insulin-feedback via PI3K-C2α activated PKBα/Akt1 is required for glucose-stimulated insulin secretion

AU - Leibiger, Barbara

AU - Moede, Tilo

AU - Uhles, Sabine

AU - Barker, Christopher J.

AU - Creveaux, Marion

AU - Domin, Jan

AU - Berggren, Per Olof

AU - Leibiger, Ingo B.

PY - 2010/6/1

Y1 - 2010/6/1

N2 - 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.

AB - 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.

KW - Biosensors

KW - Diabetes mellitus

KW - Fluorescence microscopy

KW - Insulin signaling

UR - http://www.scopus.com/inward/record.url?scp=77953516805&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953516805&partnerID=8YFLogxK

U2 - 10.1096/fj.09-148072

DO - 10.1096/fj.09-148072

M3 - Article

C2 - 20061534

AN - SCOPUS:77953516805

VL - 24

SP - 1824

EP - 1837

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 6

ER -