Dataset Information

PI3 kinases p110? and PI3K-C2? negatively regulate cAMP via PDE3/8 to control insulin secretion in mouse and human islets.

ABSTRACT:

Objectives

Phosphatidylinositol-3-OH kinase (PI3K) signalling in the endocrine pancreas contributes to glycaemic control. However, the mechanism by which PI3K modulates insulin secretion from the pancreatic beta cell is poorly understood. Thus, our objective was two-fold; to determine the signalling pathway by which acute PI3K inhibition enhances glucose-stimulated insulin secretion (GSIS) and to examine the role of this pathway in islets from type-2 diabetic (T2D) donors.

Methods

Isolated islets from mice and non-diabetic or T2D human donors, or INS 832/13 cells, were treated with inhibitors of PI3K and/or phosphodiesterases (PDEs). The expression of PI3K-C2? was knocked down using siRNA. We measured insulin release, single-cell exocytosis, intracellular Ca(2+) responses ([Ca(2+)]i) and Ca(2+) channel currents, intracellular cAMP concentrations ([cAMP]i), and activation of cAMP-dependent protein kinase A (PKA) and protein kinase B (PKB/AKT).

Results

The non-specific PI3K inhibitor wortmannin amplifies GSIS, raises [cAMP]i and activates PKA, but is without effect in T2D islets. Direct inhibition of specific PDE isoforms demonstrates a role for PDE3 (in humans and mice) and PDE8 (in mice) downstream of PI3K, and restores glucose-responsiveness of T2D islets. We implicate a role for the Class II PI3K catalytic isoform PI3K-C2? in this effect by limiting beta cell exocytosis.

Conclusions

PI3K limits GSIS via PDE3 in human islets. While inhibition of p110? or PIK-C2? signalling per se, may promote nutrient-stimulated insulin release, we now suggest that this signalling pathway is perturbed in islets from T2D donors.

SUBMITTER: Kolic J

PROVIDER: S-EPMC4921792 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Publications

PI3 kinases p110α and PI3K-C2β negatively regulate cAMP via PDE3/8 to control insulin secretion in mouse and human islets.

Kolic Jelena J Manning Fox Jocelyn E JE Chepurny Oleg G OG Spigelman Aliya F AF Ferdaoussi Mourad M Schwede Frank F Holz George G GG MacDonald Patrick E PE

Molecular metabolism 20160511 7

<h4>Objectives</h4>Phosphatidylinositol-3-OH kinase (PI3K) signalling in the endocrine pancreas contributes to glycaemic control. However, the mechanism by which PI3K modulates insulin secretion from the pancreatic beta cell is poorly understood. Thus, our objective was two-fold; to determine the signalling pathway by which acute PI3K inhibition enhances glucose-stimulated insulin secretion (GSIS) and to examine the role of this pathway in islets from type-2 diabetic (T2D) donors.<h4>Methods</h4 ...[more]

PMID: 27408772

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